Co-reporter:Li Xu, Jin Wang
Journal of Theoretical Biology 2017 Volume 422(Volume 422) pp:
Publication Date(Web):7 June 2017
DOI:10.1016/j.jtbi.2017.04.013
•Landscape and curl flux as the driving forces of multi-locus evolution.•Landscape as Lyapunov function for global stability of multi-locus evolution.•Recombination and epistasis as sources of nonequilibriumness leading to non-zero flux.Exploration of multi-locus evolution is critically important for understanding evolutionary dynamics. Recombination and epistasis lead to complex evolutionary dynamics. Quantifying the stability and function of such multi-locus evolutionary systems globally is a long-standing challenge for evolutionary biologists. The conventional Wright, Fisher and quasi-linkage equilibrium (QLE) theories can only be applied to highly restricted, simplified and special evolutionary scenarios. In this study, we developed a non-equilibrium potential and flux landscape theory to explore the multi-locus evolution beyond Wright, Fisher and the QLE. We found that the intrinsic potential landscape as a Lyapunov function under the zero noise limit can be used to describe the global stability of a deterministic multi-locus system. We identified and quantified two driving forces responsible for multi-locus evolution: the underlying landscape and the curl flux. We studied the evolution of different cases under recombination, epistasis and mutation. Recombination, frequency-dependent selection and mutation can give rise to non-zero curl flux. In particular, we investigated the dynamics of a simple example of a two-locus system. We explored the underlying potential landscape which shows stable basins attracting the system down to valleys and rotating curl flux, which aids the global communication under recombination, epistasis and mutation. Discontinuities in the first derivative of the non-equilibrium free energy functional shows the non-equilibrium phase transition as the recombination rate increases. We also explored the effect of epistasis on mono-stability and bi-stability evolution. Mutation may drive the system far from equilibrium and be another source of non-zero probability flux. Entropy production rate can quantify energy consumption or dissipation. We explained the origin of the Red Queen hypothesis for endless evolution using the curl flux. Our landscape and flux framework can be applied more generally to multi-locus evolutionary systems experiencing recombination and epistasis.
Co-reporter:Xu Shang;Wenting Chu;Xiakun Chu;Chuanbo Liu;Liufang Xu
Molecular BioSystems (2005-Present) 2017 vol. 13(Issue 10) pp:2152-2159
Publication Date(Web):2017/09/26
DOI:10.1039/C7MB00103G
The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. Although there are several studies on the binding process of Chz.core, the detailed coupled binding–folding processes are still elusive. In this study, we explored the coupled binding–folding mechanism and the effect of flexibility by continuously monitoring the flexibility degree of Chz.core. We applied an all-atom structure-based model (SBM), which takes advantage of providing both backbone and sidechain information about the conformational changes of Chz.core during binding. We presented a somewhat different “fly-casting” picture that the long IDP can undergo a tertiary stretching and bending with larger capture radii than ordered proteins. Our results suggest that the higher flexibility of Chz.core contributes to the shorter times for capturing events, leading to higher recognition efficiencies. In addition, compared to the ordered proteins, the high flexibility of the intrinsically disordered protein enables Chz.core to have a lower binding barrier and a faster association rate, which are favorable for the binding process to its partner H2A.z–H2B.
Co-reporter:Kun Zhang, Jin Wang
Physica A: Statistical Mechanics and its Applications 2017 Volume 482(Volume 482) pp:
Publication Date(Web):15 September 2017
DOI:10.1016/j.physa.2017.04.059
The economy is open and never in true equilibrium due to the exchanges with outside. However, most of the quantitative studies have been focused on the equilibrium economy. Despite of the recent efforts, it is still challenging to formulate a quantitative theory for uncovering the principles of non-equilibrium open economy. In this study, we developed a landscape and flux theory for non-equilibrium economy. We quantified the states of economy and identify the multi-stable states as the basins of attractions on the underlying landscape. We found the global driving force of the non-equilibrium economy is determined by both the underlying landscape gradient and the curl probability flux measuring the degree of non-equilibriumness through the detailed balance breaking. The non-equilibrium thermodynamics, the global stability, the optimal path and speed of the non-equilibrium economy can be formulated and quantified. In the conventional economy, the supply and demand usually has only one equilibrium. By considering nonlinear supply–demand dynamics, we found that both bi-stable states and limit cycle oscillations can emerge. By shifting the slope of demand curve, we can see how the bi-stability transforms to the limit cycle dynamics and vice versa. By parallel shifting the demand curve, we can also see how the monopoly, the competition, and the bistable monopoly and competition states emerge and transform to one other. We can also see how the mono-stable monopoly, the limit cycle and the mono-stable competition states emerge and transform to one another.
Co-reporter:Baoji Du, Dan Li, Jin Wang, Erkang Wang
Advanced Drug Delivery Reviews 2017 Volume 118(Volume 118) pp:
Publication Date(Web):1 September 2017
DOI:10.1016/j.addr.2017.04.002
Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting prodrugs into drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization. The existing MEMs can be classified into three categories: catalytic core-scaffold MEM (csMEM), nanoparticle MEM (npMEMs) and metal-organic framework (MOF) MEM (mofMEM). These MEMs can mimic diverse functions corresponding to natural enzymes, and some of which are potentially used in prodrug activation, such as DNase, RNase, carbonate esterase, etc. In this review, we briefly summarize the MEMs according to their structure and composition, and highlight the successful and potential applications for prodrug activation mediated by hydrolase-like and oxidoreductase-like MEMs.Download high-res image (221KB)Download full-size image
Co-reporter:Chun Tang, Linfeng Gan, Rong Zhang, Wenbo Lu, Xiue Jiang, Abdullah M. Asiri, Xuping Sun, Jin Wang, and Liang Chen
Nano Letters 2016 Volume 16(Issue 10) pp:6617-6621
Publication Date(Web):September 27, 2016
DOI:10.1021/acs.nanolett.6b03332
Replacement of precious Pt with earth-abundant electrocatalysts for the hydrogen evolution reaction (HER) holds great promise for clean energy devices, but the development of low-cost and durable HER catalysts with Pt-like activity is still a huge challenge. In this communication, we report on the development of self-standing ternary FexCo1–xP nanowire array on carbon cloth (FexCo1–xP/CC) as a Pt-free HER catalyst with activities being strongly related to Fe substitution ratio. Electrochemical tests show that Fe0.5Co0.5P/CC not only possesses Pt-like activity with the need of overpotential of only 37 mV to drive 10 mA cm–2, outperforming all non-noble-metal HER catalysts reported to date, but demonstrates superior long-term durability in 0.5 M H2SO4. Density functional theory calculations further reveal that Fe substitution of Co in CoP leads to more optimal free energy of hydrogen adsorption to the catalyst surface. This study offers us a promising flexible monolithic catalyst for practical applications.Keywords: CoP; density functional theory; electrocatalyst; hydrogen evolution reaction; Ternary;
Co-reporter:Xiliang Zheng and Jin Wang
Physical Chemistry Chemical Physics 2016 vol. 18(Issue 12) pp:8570-8578
Publication Date(Web):25 Feb 2016
DOI:10.1039/C5CP06416C
We investigated the main universal statistical distributions of single molecular recognition. The distributions of the single molecule binding free energy spectrum or density of states were characterized in the ligand–receptor binding energy landscape. The analytical results are consistent with the microscopic molecular simulations. The free energy distribution of different binding modes or states for a single molecule ligand receptor pair is approximately Gaussian near the mean and exponential at the tail. The equilibrium constant of single molecule binding is log-normal distributed near the mean and power law distributed near the tail. Additionally, we found that the kinetics distribution of single molecule ligand binding can be characterized by log-normal around the mean and power law distribution near the tail. This distribution is caused by exploration of the underlying inhomogeneous free energy landscape. Different ligand–receptor binding complexes have the same universal form of distribution but differ in parameters.
Co-reporter:Peiyan Bi, Wei Hong, Changshuai Shang, Jin Wang and Erkang Wang
RSC Advances 2016 vol. 6(Issue 15) pp:12486-12490
Publication Date(Web):18 Jan 2016
DOI:10.1039/C5RA26823K
In this study, bimetallic PdRu nanosponges with regulated Pd/Ru ratios have been obtained through a simple mixing pathway. The synthetic step is simple, and proceeds just by mixing PdCl2 and RuCl3 aqueous solutions into NaBH4 solution. The physical structure and chemical composition of the as-prepared nanosponges have been examined using different methods. Ethylene glycol electrooxidation reaction tests reveal the fine catalytic performance of the nanosponges, and the introduction of an appropriate amount of Ru can promote the catalytic ability of Pd. The developed synthetic pathway and the prepared materials in this contribution lead to a new practical advancement of electrocatalysts for ethylene glycol electrooxidation.
Co-reporter:Hong Qian, Ping Ao, Yuhai Tu, Jin Wang
Chemical Physics Letters 2016 Volume 665() pp:153-161
Publication Date(Web):16 November 2016
DOI:10.1016/j.cplett.2016.10.059
•Dynamics linking fast microscopic movements, intra-basin-motion, and slow inter-basin transitions.•Inter-basin transition rates exponentially dependent upon the size of the system.•Inter-basin transition as a dynamic symmetry breaking.•Fast dynamics represented by a stochastic process and the mid-level by a nonlinear dynamics.•Distinct features of taking different orders of infinite time and infinite size limits.By integrating four lines of thoughts: symmetry breaking originally advanced by Anderson, bifurcation from nonlinear dynamical systems, Landau’s phenomenological theory of phase transition, and the mechanism of emergent rare events first studied by Kramers, we introduce a possible framework for understanding mesoscopic dynamics that links (i) fast microscopic (lower level) motions, (ii) movements within each basin-of-attraction at the mid-level, and (iii) higher-level rare transitions between neighboring basins, which have slow rates that decrease exponentially with the size of the system. In this mesoscopic framework, the fast dynamics is represented by a rapidly varying stochastic process and the mid-level by a nonlinear dynamics. Multiple attractors arise as emergent properties of the nonlinear systems. The interplay between the stochastic element and nonlinearity, the essence of Kramers’ theory, leads to successive jump-like transitions among different basins. We argue each transition is a dynamic symmetry breaking, with the potential of exhibiting Thom-Zeeman catastrophe as well as phase transition with the breakdown of ergodicity (e.g., cell differentiation). The slow-time dynamics of the nonlinear mesoscopic system is not deterministic, rather it is a discrete stochastic jump process. The existence of these discrete states and the Markov transitions among them are both emergent phenomena. This emergent stochastic jump dynamics then serves as the stochastic element for the nonlinear dynamics of a higher level aggregates on an even larger spatial and slower time scales (e.g., evolution). This description captures the hierarchical structure outlined by Anderson and illustrates two distinct types of limit of a mesoscopic dynamics: A long-time ensemble thermodynamics in terms of time t→∞t→∞ followed by the size of the system N→∞N→∞, and a short-time trajectory steady state with N→∞N→∞ followed by t→∞t→∞. With these limits, symmetry breaking and cusp catastrophe are two perspectives of the same mesoscopic system on different time scales.
Co-reporter:Zhiqiang Yan
Journal of Computer-Aided Molecular Design 2016 Volume 30( Issue 3) pp:219-227
Publication Date(Web):2016 March
DOI:10.1007/s10822-016-9897-0
Scoring functions of protein–ligand interactions are widely used in computationally docking software and structure-based drug discovery. Accurate prediction of the binding energy between the protein and the ligand is the main task of the scoring function. The accuracy of a scoring function is normally evaluated by testing it on the benchmarks of protein–ligand complexes. In this work, we report the evaluation analysis of an improved version of scoring function SPecificity and Affinity (SPA). By testing on two independent benchmarks Community Structure-Activity Resource (CSAR) 2014 and Comparative Assessment of Scoring Functions (CASF) 2013, the assessment shows that SPA is relatively more accurate than other compared scoring functions in predicting the interactions between the protein and the ligand. We conclude that the inclusion of the specificity in the optimization can effectively suppress the competitive state on the funnel-like binding energy landscape, and make SPA more accurate in identifying the “native” conformation and scoring the binding decoys. The evaluation of SPA highlights the importance of binding specificity in improving the accuracy of the scoring functions.
Co-reporter:Yongliang Yang, Guohui Li, Dongyu Zhao, Haoyang Yu, Xiliang Zheng, Xiangda Peng, Xiaoe Zhang, Ting Fu, Xiaoqing Hu, Mingshan Niu, Xuefei Ji, Libo Zou and Jin Wang
Chemical Science 2015 vol. 6(Issue 5) pp:2812-2821
Publication Date(Web):13 Jan 2015
DOI:10.1039/C4SC03416C
Cognition and memory impairment are hallmarks of the pathological cascade of various neurodegenerative disorders. Herein, we developed a novel computational strategy with two-dimensional virtual screening for not only affinity but also specificity. We integrated the two-dimensional virtual screening with ligand screening for 3D shape, electrostatic similarity and local binding site similarity to find existing drugs that may reduce the signs of cognitive deficits. For the first time, we found that pazopanib, a tyrosine kinase inhibitor marketed for cancer treatment, inhibits acetylcholinesterase (AchE) activities at sub-micromolar concentration. We evaluated and compared the effects of intragastrically-administered pazopanib with donepezil, a marketed AchE inhibitor, in cognitive and behavioral assays including the novel object recognition test, Y maze and Morris water maze test. Surprisingly, we found that pazopanib can restore memory loss and cognitive dysfunction to a similar extent as donepezil in a dosage of 15 mg kg−1, only one fifth of the equivalent clinical dosage for cancer treatment. Furthermore, we demonstrated that pazopanib dramatically enhances the hippocampal Ach levels and increases the expression of the synaptic marker SYP. These findings suggest that pazopanib may become a viable treatment option for memory and cognitive deficits with a good safety profile in humans.
Co-reporter:Wei Hong, Changshuai Shang, Jin Wang and Erkang Wang
Nanoscale 2015 vol. 7(Issue 22) pp:9985-9989
Publication Date(Web):05 May 2015
DOI:10.1039/C5NR01679G
In this work, by utilizing galvanic replacement reaction, a simple method for the synthesis of trimetallic PtCuCo hollow nanospheres with a dendritic shell is demonstrated. The compositions of the nanospheres can be well controlled, and the electrocatalytic activity can also be modulated by adjusting their compositions. Electrocatalytic results show that all of the as-prepared trimetallic PtCuCo nanomaterials show better catalytic performance toward ethylene glycol electrooxidation than the commercial catalyst.
Co-reporter:Changshuai Shang, Wei Hong, Jin Wang, Erkang Wang
Journal of Power Sources 2015 Volume 285() pp:12-15
Publication Date(Web):1 July 2015
DOI:10.1016/j.jpowsour.2015.03.092
•Carbon supported Pt-free NiPdAu hollow nanoparticles have been prepared.•Ni nanospheres are used as sacrificial template.•NiPdAu hollow nanoparticles exhibit narrow size distribution.•The as-synthesized catalysts show superior electrocatalytic activity.In this paper, Ni nanoparticles (NPs) are prepared in an aqueous solution by using sodium borohydride as reducing agent. With Ni NPs as the sacrificial template, hollow NiPdAu NPs are successfully prepared via partly galvanic displacement reaction between suitable metal precursors and Ni NPs. The as-synthesized hollow NiPdAu NPs can well dispersed on the carbon substrate. Transmission electron microscopy, X-ray diffraction and inductively coupled plasma mass spectrometry are taken to analyze the morphology, structure and composition of the as-synthesized catalysts. The prepared catalysts show superior catalytic activity and stability for methanol electrooxidation in alkaline media compared with commercial Pd/C and Pt/C. Catalysts prepared in this work show great potential to be anode catalysts in direct methanol fuel cells.
Co-reporter:Jiyang Liu, Tianshu Wang, Jin Wang, Erkang Wang
Electrochimica Acta 2015 Volume 161() pp:17-22
Publication Date(Web):10 April 2015
DOI:10.1016/j.electacta.2015.02.034
•Outstanding 3D biosensing platform was explored for reagentless detection of H2O2.•Monolithic 3D graphene foam served as a freestanding electrode scaffold.•MB-CNTs hybrid assembled on 3D graphene as efficient electron mediator.•Mussel inspired polydopamine as a green linker for enzyme immobilization.A simple and versatile method is described to construct high performance three-dimensional (3D) graphene-based enzyme biosensor. Monolithic and macroporous 3D graphene foam grown by chemical vapor deposition (CVD) was used as a freestanding electrode for co-immobilization of horseradish peroxidase (HRP) and a commonly used redox mediator, methylene blue (MB). Carbon nanotubes (CNTs) were employed as carriers of MB molecules to immobilize them on 3D graphene surface through strong π-π stacking force. Mussel-inspired biopolymer polydopamine (PDA) was formed by in-situ polymerization and served as a green linker, which could covalently graft HRP on the surface of 3D graphene/MB-CNTs electrode. In addition, PDA layer could also effectively prevent the leakage of inner electron mediators. Owing to the 3D macroporous architecture, exceptional properties of graphene and surface-bound mediators, the biosensor demonstrated outstanding performance for reagentless detection of H2O2 in terms of wide linear range (0.2 μM to 1.1 mM), high sensitivity (227.8 μA mM−1 cm−2), low detection limit (58.0 nM), and fast response (reaching 95% of the steady current within 3 s). The biosensor exhibited high reproducibility and stability.
Co-reporter:Tianshu Wang, Jiyang Liu, Xiaoxiao Gu, Dan Li, Jin Wang, Erkang Wang
Analytica Chimica Acta 2015 Volume 882() pp:32-37
Publication Date(Web):2 July 2015
DOI:10.1016/j.aca.2015.05.008
•Fc-PAH was modified on the surface of graphene to prepare hybid nanocomposite (Fc-PAH-G).•A cytosensor was constructed with Fc-PAH-G, PSS and aptamer AS1411 by LBL technology.•The sensing interface introduced more redox probe and enhanced current signal on electrode.•The sensor showed a detection range of 10–106 cells/mL with a detection limit of 10 cells/mL.Here, a cytosensor was constructed with ferrocene-appended poly(allylamine hydrochloride) (Fc-PAH) functionalized graphene (Fc-PAH-G), poly(sodium-p-styrenesulfonate) (PSS) and aptamer (AS1411) by layer-by-layer assembly technology. The hybrid nanocomposite Fc-PAH-G not only brings probes on the electrode and also promotes electron transfer between the probes and the substrate electrode. Meanwhile, LBL technology provides more effective probes to enhance amplified signal for improving the sensitivity of the detection. While AS1411 forming G-quardruplex structure and binding cancer cells, the current response of the sensing electrode decreased due to the insulating properties of cellular membrane. Differential pulse voltammetry (DPV) was performed to investigate the electrochemical detection of HeLa cells attributing to its sensitivity of the current signal change. The as-prepared aptasensor showed a high sensitivity and good stability, a widely detection range from 10 to 106 cells/mL with a detection limit as low as 10 cells/mL for the detection of cancer cells.
Co-reporter:Zhedong Zhang and Jin Wang
Physical Chemistry Chemical Physics 2015 vol. 17(Issue 37) pp:23754-23760
Publication Date(Web):14 Aug 2015
DOI:10.1039/C5CP03623B
We analytically investigate the population and coherence dynamics and relaxations in the vibrational energy transport in molecules. The corresponding two time scales t1 and t2 are explored. Coherence-population entanglement is found to considerably promote the time scale t2 for dephasing and the amplitude of coherence. This is attributed to the suppression of the environment-induced drift force by coherence. Moreover the population imbalance (magnetization) is shown to be significantly amplified with the coherence-population entanglement. Contrary to the previous studies, we exactly elucidate a coherent process by showing t1 < t2. We predict the relaxation of vibrational and orientational dynamics of OH-stretching modes in agreement with the recent experiments, when applied to the water molecules dissolved in D2O. Finally we explore the coherence effect on the heat current at the macroscopic level.
Co-reporter:Jiangtao Ren, Tianshu Wang, Erkang Wang and Jin Wang
Analyst 2015 vol. 140(Issue 8) pp:2556-2572
Publication Date(Web):03 Feb 2015
DOI:10.1039/C4AN02282C
G-quadruplex (G4), as one of the significant functional nucleic acids (FNAs), has attracted researchers’ wide attention, and in particular has been employed for the construction of label-free molecular sensors and logic systems based on the peroxidase-like activity of the G4–hemin complex and G4-enhanced luminescence of G4-binding organic dyes. Its cation-dependent conformation and stability provide opportunities for the recognition of metal ion inputs and application of a split G4 strategy. Moreover, coupling the G4 sequence with other FNAs, e.g. metal ion-dependent DNAzymes and aptamers, has prominently broadened the range of possible targets from metal ions and DNA to diverse proteins and cells. Although there are limitations, such as a low ability of anti-interference and multiplex analysis, the excellent advantages (e.g. simplicity and low cost) endow the G4-mediated strategy with tremendous potential to be further exploited for practical bioanalysis and complicated DNA computing.
Co-reporter:Cong Chen, Kun Zhang, Haidong Feng, Masaki Sasai and Jin Wang
Physical Chemistry Chemical Physics 2015 vol. 17(Issue 43) pp:29036-29044
Publication Date(Web):24 Sep 2015
DOI:10.1039/C5CP04780C
Many physical, chemical and biochemical systems (e.g. electronic dynamics and gene regulatory networks) are governed by continuous stochastic processes (e.g. electron dynamics on a particular electronic energy surface and protein (gene product) synthesis) coupled with discrete processes (e.g. hopping among different electronic energy surfaces and on and off switching of genes). One can also think of the underlying dynamics as the continuous motion on a particular landscape and discrete hoppings among different landscapes. The main difference of such systems from the intra-landscape dynamics alone is the emergence of the timescale involved in transitions among different landscapes in addition to the timescale involved in a particular landscape. The adiabatic limit when inter-landscape hoppings are fast compared to continuous intra-landscape dynamics has been studied both analytically and numerically, but the analytical treatment of the non-adiabatic regime where the inter-landscape hoppings are slow or comparable to continuous intra-landscape dynamics remains challenging. In this study, we show that there exists mathematical mapping of the dynamics on 2N discretely coupled N continuous dimensional landscapes onto one single landscape in 2N dimensional extended continuous space. On this 2N dimensional landscape, eddy current emerges as a sign of non-equilibrium non-adiabatic dynamics and plays an important role in system evolution. Many interesting physical effects such as the enhancement of fluctuations, irreversibility, dissipation and optimal kinetics emerge due to non-adiabaticity manifested by the eddy current illustrated for an N = 1 self-activator. We further generalize our theory to the N-gene network with multiple binding sites and multiple synthesis rates for discretely coupled non-equilibrium stochastic physical and biological systems.
Co-reporter:Wei Hong, Jin Wang and Erkang Wang
RSC Advances 2015 vol. 5(Issue 58) pp:46935-46940
Publication Date(Web):22 May 2015
DOI:10.1039/C5RA08300A
Herein, a simple one-pot method for the synthesis of trimetallic PdRuCo hollow nanocrystals is developed. PdRuCo hollow nanocrystals with different compositions can be obtained through a wet-chemical route, just by using a sacrificial Co nanoparticle template. The prepared nanomaterials have been analyzed by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy, etc. The prepared PdRuCo nanospheres possess an alloyed nanostructure and with an average diameter of about 49 nm. The prepared nanocrystals show much better catalytic activity for ethylene glycol and glycerol electrooxidation than that of a commercial Pd/C catalyst. The reduced cost and enhanced catalytic activity of the as-prepared Pd-based materials allow them to possess great potential applications in direct fuel cells.
Co-reporter:Zhedong Zhang and Jin Wang
The Journal of Physical Chemistry B 2015 Volume 119(Issue 13) pp:4662-4667
Publication Date(Web):March 16, 2015
DOI:10.1021/acs.jpcb.5b01569
Recently, the quantum nature in the energy transport in solar cells and light-harvesting complexes has attracted much attention as being triggered by the experimental observations. We model the light-harvesting complex (i.e., PEB50 dimer) as a quantum heat engine (QHE) and study the effect of the undamped intramolecule vibrational modes on the coherent energy-transfer process and quantum transport. We find that the exciton–vibration interaction has nontrivial contribution to the promotion of quantum yield as well as transport properties of the QHE at steady state by enhancing the quantum coherence quantified by entanglement entropy. The perfect quantum yield over 90% has been obtained, with the exciton–vibration coupling. We attribute these improvements to the renormalization of the electronic couplings effectively induced by exciton–vibration interaction and the subsequent delocalization of excitons. Finally, we demonstrate that the thermal relaxation and dephasing can help the excitation energy transfer in the PEB50 dimer.
Co-reporter:John Yao
The Journal of Physical Chemistry Letters 2015 Volume 6(Issue 11) pp:2022-2026
Publication Date(Web):May 15, 2015
DOI:10.1021/acs.jpclett.5b00524
Lambda Cro repressor is one of the best studied dimeric transcription factors. However, there has still been an unsettled debate for decades about whether it is a two-state dimer or three-state dimer. We provide a new mechanism model that can reconcile these seemingly conflicting (mutually exclusive) experimental results. From simulations with all-atom structure-based model, we observe that the dimerization process of Lambda Cro repressor starts from one folded monomer with one unfolded monomer. Intrasubunit folding and intersubunit binding are partially coupled, in a fly casting manner.
Co-reporter:Wei Hong;Erkang Wang
Nano Research 2015 Volume 8( Issue 7) pp:2308-2316
Publication Date(Web):2015 July
DOI:10.1007/s12274-015-0741-y
Using Te nanowires as a sacrificial template, we developed a facile wet-chemical method for the synthesis of bimetallic PtCu nanowires. The as-prepared PtCu nanowires possess a porous structure and high aspect ratio. Transmission electron microscopy, X-ray diffraction, energy dispersive spectroscopy, energy dispersive X-ray spectrum elemental mapping, inductively coupled plasmamass spectroscopy, and X-ray photoelectron spectroscopy (XPS) measurement techniques are used to analyze the structure and composition of the as-prepared nanowires. The XPS results verify that the incorporation of Cu led to the modified electronic state of Pt. Electrocatalytic results prove that the as-prepared nanowires present superior activity for methanol and ethanol electrooxidation in an alkaline solution.
Co-reporter:Jin Wang
PNAS 2015 Volume 112 (Issue 2 ) pp:304-305
Publication Date(Web):2015-01-13
DOI:10.1073/pnas.1423233112
Co-reporter:Jiyang Liu, Jiao Wang, Tianshu Wang, Dan Li, Fengna Xi, Jin Wang, Erkang Wang
Biosensors and Bioelectronics 2015 Volume 65() pp:281-286
Publication Date(Web):15 March 2015
DOI:10.1016/j.bios.2014.10.016
•Immunosensor based on monolithic 3D graphene was prepared for the first time.•3D graphene was functionalized by in-situ polymerization of dopamine.•Polydopamine layer imparts 3D graphene with well hydrophilicity and modifiability.•Lectin grafted on polydopamine was used to immobilize sugar-protein labeled Ab.•A wide detection range of 0.1–750.0 ng ml−1 was reached.A high performance three-dimensional (3D) electrochemical immunosensor was developed for sensitive detection of the tumor biomarker, carcinoembryonic antigen (CEA). Monolithic and macroporous graphene foam grown by chemical vapor deposition (CVD) served as the scaffold of the free-standing 3D electrode. Immuno-recognition interface was fabricated via simple and non-covalent immobilization of antibody using lectin-mediated strategy. Briefly, the well-known lectin macromolecule (concanavalin A, Con A) monolayer was functionalized on 3D graphene (3D-G) using in-situ polymerized polydopamine as the linker. Then the widely used horseradish peroxidase (HRP)-labeled antibody (anti-CEA) in immunoassays was efficiently immobilized to demonstrate the recognition interface via the biospecific affinity of lectin with sugarprotein. The 3D immunosensor is able to detect CEA with a wide linear range (0.1–750.0 ng ml−1), low detection limit (~90 pg ml−1 at a signal-to-noise ratio of 3), and short incubation time (30 min). Furthermore, this biosensor was used for the detection of the CEA level in real serum samples.
Co-reporter:Tianshu Wang, Jiyang Liu, Jiangtao Ren, Jin Wang, Erkang Wang
Talanta 2015 Volume 143() pp:438-441
Publication Date(Web):1 October 2015
DOI:10.1016/j.talanta.2015.05.022
•Phospholipids-AuNPs-graphene biocomposite (PLs-AuNPs-G) was prepared.•PLs-AuNPs-G was demonstrated as an effective matrix for MP-11 immobilization.•A third generation biosensor based on PLs-AuNPs-G was constructed for H2O2 detection.•The biosensor exhibited high sensitivity and good stability.•The biosensor realized real-time detection of H2O2 released from living cells.A hybrid composite constructed of phospholipids bilayer membrane, gold nanoparticles and graphene was prepared and used as matrices for microperoxidase-11 (MP11) immobilization. The direct electrochemistry and corresponding bioelectrocatalysis of the enzyme electrode was further investigated. Phospholipid bilayer membrane protected gold nanoparticles (AuNPs) were assembled on polyelectrolyte functionalized graphene sheets through electrostatic attraction to form a hybrid bionanocomposite. Owing to the biocompatible microenvironment provided by the mimetic biomembrane, microperoxidase-11 entrapped in this matrix well retained its native structure and exhibited high bioactivity. Moreover, the AuNPs–graphene assemblies could efficiently promote the direct electron transfer between the immobilized MP11 and the substrate electrode. The as-prepared enzyme electrode presented good direct electrochemistry and electrocatalytic responses to the reduction of hydrogen peroxide (H2O2). The resulting H2O2 biosensor showed a wide linear range (2.0×10−5–2.8×10−4 M), a low detection limit (2.6×10−6 M), good reproducibility and stability. Furthermore, this sensor was used for real-time detection of H2O2 dynamically released from the tumor cells MCF-7 in response to a pro-inflammatory stimulant.A hybrid composite constructed of phospholipids bilayer membrane, gold nanoparticles and graphene was prepared and used as matrices for microperoxidase-11 (MP11) immobilization. The composites promoted the direct electron transfer between MP11 and the underlying electrode. Moreover, the biosensor successfully realized the detection of H2O2 releasing from cancer cells.
Co-reporter:Haidong Feng, Kun Zhang and Jin Wang
Chemical Science 2014 vol. 5(Issue 10) pp:3761-3769
Publication Date(Web):26 Jun 2014
DOI:10.1039/C4SC00831F
Transition state or Kramers' rate theory has been used to quantify the kinetic speed of many chemical, physical and biological equilibrium processes successfully. For non-equilibrium systems, the analytical quantification of the kinetic rate is still challenging. We developed a new transition state or Kramers' rate theory for general non-equilibrium stochastic systems with finite fluctuations. We illustrated that the non-equilibrium rate is mainly determined by the exponential factor as the weight action measured from the basin of attraction to the “saddle” or more accurately “global maximum” point on the optimal path rather than the saddle point of the underlying landscape as in the conventional transition state or Kramers' rate formula for equilibrium systems. Furthermore, the pre-factor of the non-equilibrium rate is determined by the fluctuations around the basin of attraction and “saddle” point along the optimal paths. We apply our theory for non-equilibrium rate to fate decisions in stem cell differentiation. The dominant kinetic paths between stem and differentiated cell basins are irreversible and do not follow the gradient path along the landscape. This reflects that the dynamics of non-equilibrium systems is not only determined by the landscape gradient but also the curl flux, suggesting experiments to test theoretical predictions. We calculated the transition rate between cell fates. The predictions are in good agreements with stochastic simulations. Our general rate and path formula can be applied to other non-equilibrium systems.
Co-reporter:Jiyang Liu, Xiaohui Wang, Tianshu Wang, Dan Li, Fengna Xi, Jin Wang, and Erkang Wang
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 22) pp:19997
Publication Date(Web):November 10, 2014
DOI:10.1021/am505547f
Biological modification of monolithic and porous 3D graphene is of great significance for extending its application in fabricating highly sensitive biosensors. The present work reports on the first biofunctionalization of monolithic and freestanding 3D graphene foam for one-step preparation of reagentless enzymatic biosensors by controllable chitosan (CS) electrodeposition technology. Using a homogeneous three-component electrodeposition solution containing a ferrocene (Fc) grafted CS hybrid (Fc-CS), glucose oxidase (GOD), and single-walled carbon nanotubes (SWNTs), a homogeneous biocomposite film of Fc-CS/SWNTs/GOD was immobilized on the surface of 3D graphene foam by one-step electrodeposition. The Fc groups grafted on chitosan can be stably immobilized on the 3D graphene surface and keep their original electrochemical activity. The SWNTs doped into the Fc-CS matrix act as a nanowire to facilitate electron transfer and improve the conductivity of the biocomposite film. Combined with the extraordinary properties of 3D graphene foam including large active surface area, high conductivity, and fast mass transport dynamics, the 3D graphene based enzymatic biosensor achieved a large linear range (5.0 μM to 19.8 mM), a low detection limit (1.2 μM), and rapid response (reaching the 95% steady-state response within 8 s) for reagentless detection of glucose in the phosphate buffer solution.Keywords: 3D graphene; biosensor; chitosan electrodeposition; enzyme; reagentless
Co-reporter:Wei Hong, Jin Wang, and Erkang Wang
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 12) pp:9481
Publication Date(Web):April 28, 2014
DOI:10.1021/am501859k
In recent years, direct ethanol fuel cells (DEFCs) are attracting increasing attention owing to their wide applications. However, a significant challenge in the development of DEFC technology is the urgent need for highly active anode catalysts for the ethanol oxidation reaction. In this work, a facile and reproducible method for the high-yield synthesis of PdAu nanowire networks is demonstrated. The whole synthetic process is very simple, just mixing Na2PdCl4, HAuCl4, and KBr in an aqueous solution and using polyvinylpyrrolidone as a protective reagent while sodium borohydride as a reductant. The whole synthetic process can be simply performed at room temperature and completed in 30 min, which can greatly simplify the synthetic process and lower the preparation cost. Electrochemical catalytic measurement results prove that the as-prepared catalysts exhibit dramatically enhanced electrocatalytic activity for ethanol electrooxidation in alkaline solution. The facile synthetic process and excellent catalytic performance of the as-prepared catalysts demonstrate that they can be used as a promising catalyst for DEFCs.Keywords: electrooxidation; ethanol; gold; nanowire networks; palladium;
Co-reporter:Wei Hong, Youxing Fang, Jin Wang, Erkang Wang
Journal of Power Sources 2014 Volume 248() pp:553-559
Publication Date(Web):15 February 2014
DOI:10.1016/j.jpowsour.2013.09.126
•Porous Pd nanoparticles have been synthesized by a simple method.•The developed method is efficient, rapid and convenient.•Hydroquinone was used as the reductant to obtain porous Pd nanoparticles.•The as-prepared catalysts exhibit excellent electrocatalytic activity.Porous Pd nanoparticles are successfully prepared by a rapid, one-step, and efficient route with high yield in aqueous solution. The developed method is very simple, just by mixing sodium tetrachloropalladate, polyvinylpyrrolidone and hydroquinone and heated at 70 °C for 15 min. The structure and composition are analyzed by transmission electron microscope, selected-area electron diffraction, inductively coupled plasma optical emission spectrometer, X-ray diffraction, energy dispersive X-ray spectrum and X-ray photoelectron spectroscopy. Electrochemical catalytic measurement results prove that the as synthesized porous Pd nanoparticles exhibit superior catalytic activity towards ethanol and formic acid electrooxidation.
Co-reporter:Wei Hong, Changshuai Shang, Jin Wang, Erkang Wang
Electrochemistry Communications 2014 Volume 48() pp:65-68
Publication Date(Web):November 2014
DOI:10.1016/j.elecom.2014.08.017
•Dendritic PdAu nanoparticles have been synthesized by a simple method.•The synthetic method is effective, rapid and convenient.•Hydroquinone was used as the reductant to obtain dendritic PdAu nanoparticles.•The as-prepared nanocrystals present superior electrocatalytic activity.A facile method for the rapid synthesis of dendritic PdAu alloyed bimetallic nanocrystals is demonstrated. The whole synthetic process is very simple just by mixing Na2PdCl4, HAuCl4, polyvinylpyrrolidone and hydroquinone and heated at 50 °C for 15 min. The as-prepared dendritic PdAu nanoparticles exhibit superior catalytic activity for methanol, ethanol and glycerol electrooxidation in alkaline solution, and their catalytic performance is composition-dependent.
Co-reporter:Zaizhi Lai, Kun Zhang and Jin Wang
Physical Chemistry Chemical Physics 2014 vol. 16(Issue 14) pp:6486-6495
Publication Date(Web):17 Feb 2014
DOI:10.1039/C3CP54476A
We explore the multi-dimensional diffusion dynamics of protein conformational change. We found in general that the diffusion is anisotropic and inhomogeneous. The directional and positional dependence of diffusion have significant impacts on the protein conformational kinetics: the dominant kinetic path of conformational change is shifted from the naively expected steepest decent gradient paths. The kinetic transition state is shifted away from the transition state. The effective kinetic free energy barrier height, determining the kinetic rate of the conformational change, is shifted away from the one estimated from the thermodynamic free energy barrier. The shift of the transition state in position and value will modify the phi value analysis for identification of hot residues and interactions responsible for conformational dynamics. Ongoing and future experiments can test the predictions of the model.
Co-reporter:Wei Hong, Jin Wang, Erkang Wang
International Journal of Hydrogen Energy 2014 Volume 39(Issue 7) pp:3226-3230
Publication Date(Web):25 February 2014
DOI:10.1016/j.ijhydene.2013.12.096
•Pd nanowires have been synthesized in the presence of bromide ions.•PVP were used as protective reagents while NaBH4 as the reductant.•The as-prepared Pd nanowires were well dispersed on carbon.•The as-prepared catalyst exhibits excellent electrocatalytic activity.•The developed method is very simple, rapid and convenient.Palladium nanowires with a diameter of about 5 nm and length of a few tens of nanometers can be synthesized in the presence of large amount of bromide ions, employing polyvinylpyrrolidone as protective reagent while sodium borohydride as reductant. The obtained Pd nanowires are well dispersed on Vulcan XC-72 carbon. The structure and composition of the as-prepared catalyst are analyzed by transmission electron microscope, X-ray diffraction, energy dispersive X-ray spectrum and inductively coupled plasma optical emission spectrometer. Electrochemical catalytic measurement results prove that the as-prepared catalyst exhibits superior electrocatalytic activity towards ethanol and formic acid electrooxidation.
Co-reporter:Feng Zhang, Liufang Xu, Jin Wang
Chemical Physics Letters 2014 Volume 599() pp:38-43
Publication Date(Web):18 April 2014
DOI:10.1016/j.cplett.2014.03.011
•Extinction phenomena are studied through the potential–flux landscape theory.•Disease extinction is investigated through an epidemic model.•Mutualism or parasitism is formed between mother and daughter pathogen species.•Speciation towards low virulence reduces the extinction risk for a pathogen species.We apply the potential–flux landscape theory to deal with the large fluctuation induced extinction phenomena. We quantify the most probable extinction pathway on the landscape and measure the extinction risk by the landscape topography. In this Letter, we investigate the disease extinction through an epidemic model described by a set of chemical reaction. We found the virulence-differential-dependent symbioses between mother and daughter pathogen species: mutualism and parasitism. The symbioses, whether mutualism or parasitism, benefit the higher virulence species. This implies that speciation towards lower virulence is an effective strategy for a pathogen species to reduce its extinction risk.
Co-reporter:Feng Zhang, Liufang Xu, Jin Wang
Chemical Physics Letters 2014 Volume 603() pp:51
Publication Date(Web):30 May 2014
DOI:10.1016/j.cplett.2014.04.032
Co-reporter:Zaizhi Lai;Jun Jiang;Shaul Mukamel
Israel Journal of Chemistry 2014 Volume 54( Issue 8-9) pp:1394-1403
Publication Date(Web):
DOI:10.1002/ijch.201300141
Abstract
Ultraviolet (UV) spectra of proteins originate from electronic excitations of their backbone chromophore and aromatic side chains and provide a sensitive probe of the secondary structure. Recently developed femtosecond lasers allow multidimensional spectroscopy to be extended into the UV regime. Two-dimensional UV (2DUV) techniques, with short pulses, provide a promising tool to study the structures and dynamics of proteins. We combined 2DUV spectroscopy and molecular dynamics generated free energy profiles to simulate the protein electronic transitions and UV photon echo signals to monitor the protein folding process of the small protein Beta3s. Near-ultraviolet (NUV) and far-ultraviolet (FUV) signals illustrate the variation of the 2D correlation plots when the protein evolves along the underlying free energy landscape. Chiral polarization configurations of the NUV and FUV pulses are sensitive to protein structural evolution. This work provides a protocol for applying multidimensional UV spectroscopy to study protein folding.
Co-reporter:Jun Jiang, Zaizhi Lai, Jin Wang, and Shaul Mukamel
The Journal of Physical Chemistry Letters 2014 Volume 5(Issue 8) pp:1341-1346
Publication Date(Web):March 19, 2014
DOI:10.1021/jz5002264
The function of protein relies on their folding to assume the proper structure. Probing the structural variations during the folding process is crucial for understanding the underlying mechanism. We present a combined quantum mechanics/molecular dynamics simulation study that demonstrates how coherent resonant nonlinear ultraviolet spectra can be used to follow the fast folding dynamics of a mini-protein, Trp-cage. Two dimensional ultraviolet signals of the backbone transitions carry rich information of both local (secondary) and global (tertiary) structures. The complexity of signals decreases as the conformational entropy decreases in the course of the folding process. We show that the approximate entropy of the signals provides a quantitative marker of protein folding status, accessible by both theoretical calculations and experiments.Keywords: approximate entropy; conformational entropy; protein folding; quantum mechanics/molecular dynamics; two-dimensional ultraviolet spectroscopy;
Co-reporter:Sonia Longhi;Philippe Roche;Yong Wang
PNAS 2014 Volume 111 (Issue 16 ) pp:E1559
Publication Date(Web):2014-04-22
DOI:10.1073/pnas.1400340111
Co-reporter:Chunhe Li
PNAS 2014 Volume 111 (Issue 39 ) pp:14130-14135
Publication Date(Web):2014-09-30
DOI:10.1073/pnas.1408628111
Cell cycles, essential for biological function, have been investigated extensively. However, enabling a global understanding
and defining a physical quantification of the stability and function of the cell cycle remains challenging. Based upon a mammalian
cell cycle gene network, we uncovered the underlying Mexican hat landscape of the cell cycle. We found the emergence of three
local basins of attraction and two major potential barriers along the cell cycle trajectory. The three local basins of attraction
characterize the G1, S/G2, and M phases. The barriers characterize the G1 and S/G2 checkpoints, respectively, of the cell
cycle, thus providing an explanation of the checkpoint mechanism for the cell cycle from the physical perspective. We found
that the progression of a cell cycle is determined by two driving forces: curl flux for acceleration and potential barriers
for deceleration along the cycle path. Therefore, the cell cycle can be promoted (suppressed), either by enhancing (suppressing)
the flux (representing the energy input) or by lowering (increasing) the barrier along the cell cycle path. We found that
both the entropy production rate and energy per cell cycle increase as the growth factor increases. This reflects that cell
growth and division are driven by energy or nutrition supply. More energy input increases flux and decreases barrier along
the cell cycle path, leading to faster oscillations. We also identified certain key genes and regulations for stability and
progression of the cell cycle. Some of these findings were evidenced from experiments whereas others lead to predictions and
potential anticancer strategies.
Co-reporter:Jiangtao Ren, Jiahai Wang, Jin Wang, Erkang Wang
Biosensors and Bioelectronics 2014 Volume 51() pp:336-342
Publication Date(Web):15 January 2014
DOI:10.1016/j.bios.2013.07.059
•DNA ligation was coupled to split G-quadruplex probes.•Highly selective detection of small biomolecules (ATP and NAD+) was realized.•The effect of single-base mismatch position on the ligation efficiency was also validated.•The high selectivity is attributed to cofactor/sequence-dependent activity of DNA ligase.•The non-covalent labeling strategy is simple, cost-effective and versatile.Through tuning relative thermodynamic stabilities (I, II and III), DNA ligation was coupled to split G-quadruplex probes and a versatile, non-covalent labelling and fluorescent strategy was constructed based on inhibition of template-directed G-quadruplex assembling by ligation reaction. The non-covalent complex between G-quadruplex and fluorescent probe was employed as signalling label and thus covalent modification of DNA probes with fluorescent probes was avoided. Selective detection of small biomolecules (ATP and NAD+) in the nanomolar range was realized due to the cofactor-dependent activity of DNA ligases (T4 and Escherichia coli DNA ligase). By virtue of the simple strategy, the effect of mismatch position of single-base mismatched template DNA on the ligation efficiency was validated. Meanwhile, highly mismatch-influenced ligation efficiency of ligase endows the cost-effective strategy great potential for single-nucleotide polymorphism (SNP) analysis. The non-covalent labeling strategy provides a versatile and cost-effective platform for monitor of DNA ligation, cofactor detection, SNP analysis and other ligase-based assays.
Co-reporter:Wei Hong, Jin Wang, Erkang Wang
Electrochemistry Communications 2014 40() pp: 63-66
Publication Date(Web):
DOI:10.1016/j.elecom.2013.12.026
Co-reporter:Zhiqiang Yan, Xiliang Zheng, Erkang Wang and Jin Wang
Chemical Science 2013 vol. 4(Issue 6) pp:2387-2395
Publication Date(Web):04 Apr 2013
DOI:10.1039/C3SC50478F
Binding affinity and specificity are crucial for biomolecular recognition. Past studies have focused on binding affinity while the quantification of specificity has remained an elusive challenge. The conventional specificity measures the discrimination of the specific receptor against others for a ligand binding. It is difficult to explore all the possible competing receptors for the ligand. Here, we quantified the thermodynamic intrinsic specificity of discriminating the “native” binding mode against the “non-native” binding modes. Intrinsic specificity is relatively easy to compute since one doesn't need to explore all the other receptors. We found that the thermodynamic intrinsic specificity correlates with the conventional specificity. This validates the statistical equivalence of conventional and intrinsic specificities for receptors at reasonable size. We also computationally quantified the residence time of a ligand on the receptor target as the kinetic specificity. We found that the kinetic specificity correlates with the thermodynamic intrinsic specificity and the binding affinity, suggesting the kinetics and the thermodynamics can be simultaneously optimized for biological activities. With the thermodynamic and kinetic specificities in addition to affinity, we carried out a drug screening test on the target cyclooxygenase-2 (COX-2). We showed that multidimensional (two- and three-dimensional) screening has higher capability than affinity alone to discriminate the drug target (COX-2) from the competitive receptor (COX-1), and the selective drugs from the non-selective drugs. Our work suggests a new way of multidimensional drug screening and target identification, which has significant potential applications for drug discovery and design.
Co-reporter:Wei Hong, Yaqing Liu, Jin Wang, Erkang Wang
Journal of Power Sources 2013 Volume 241() pp:751-755
Publication Date(Web):1 November 2013
DOI:10.1016/j.jpowsour.2013.05.072
•Carbon-supported hollow flower-like NiPdPt has been synthesized.•Ni nanoparticles are used as the sacrificial template to obtain NiPdPt.•NiPdPt are well assembled on carbon nanotubes through electrostatic interaction.•The as-prepared catalysts exhibit excellent electrocatalytic activity.Hollow flower-like NiPdPt nanoparticles (NPs) are prepared through galvanic replacement between Ni nanoparticles and noble metal salts. Multiwalled-carbon nanotubes (MWCNTs) can be used to support the as synthesized hollow flower-like NiPdPt NPs through electrostatic self-assembly. The structure and composition are analyzed by transmission electron microscope, X-ray diffraction and inductively coupled plasma optical emission spectrometer. Electrochemical catalytic measurement results prove that the as synthesized MWCNTs supported NiPdPt NPs present excellent catalytic activity toward ethanol electrooxidation in alkaline solution.
Co-reporter:Wei Hong, Yaqing Liu, Jin Wang, Erkang Wang
Electrochemistry Communications 2013 Volume 31() pp:59-62
Publication Date(Web):June 2013
DOI:10.1016/j.elecom.2013.03.006
•Carbon supported Pd nanoparticles has been synthesized through an ultrasonic way.•Commonly used ultrasonic cleaner was used for the ultrasonic synthesis.•Ethylene glycol was used to reduce chloropalladic acid.•No additional surfactants or protecting reagents were introduced.•The as-prepared catalysts exhibit superior electrocatalytic activity.Carbon supported Pd nanoparticles can be synthesized through an ultrasound assisted way. Chloropalladic acid can be reduced by ethylene glycol at room temperature with a commonly used ultrasonic cleaner. No additional surfactants or stabilizers were introduced. The Pd nanoparticles were well dispersed on Vulcan XC-72 carbon. The as-prepared catalysts exhibit superior electrocatalytic performance toward ethanol electrooxidation in alkaline solution. The developed method is simple, convenient, effective and environmentally friendly.
Co-reporter:Yong Wang, Linfeng Gan, Erkang Wang, and Jin Wang
Journal of Chemical Theory and Computation 2013 Volume 9(Issue 1) pp:84-95
Publication Date(Web):November 5, 2012
DOI:10.1021/ct300720s
Adenylate kinase (ADK) has been explored widely, through both experimental and theoretical studies. However, still less is known about how the functional dynamics of ADK is modulated explicitly by its natural substrates. Here, we report a quantitative study of the dynamic energy landscape for ADK responding to the substrate binding by integrating both experimental investigations and theoretical modeling. We make theoretical predictions which are in remarkable agreement with the single molecule experiments on the substrate-bound complex. With our combined models of ADK in its apo form, in the presence of AMP or ATP, and in complex with both substrates, we specifically address the following key questions: (1) Are there intermediate state(s) during their catalytic cycle and if so how many? (2) How many pathways are there along the open-to-closed transitions and what are their corresponding weights? (3) How do substrates influence the pathway weights and the stability of the intermediates? (4) Which lid’s motion is rate-limiting along the turnover cycle, the NMP or the LID domain? Our models predict two major parallel stepwise pathways and two on-pathway intermediates which are denoted as IN (NMP domain open while LID domain closed) and IL (LID domain open and NMP domain closed), respectively. Further investigation of temperature effects suggests that the IN pathway is dominant at room temperature, but the IL pathway is dominant at the optimal temperature. This leads us to propose that the IL pathway is more dominant by entropy and IN pathway by enthalpy. Remarkably, our results show that even with maximum concentrations of natural substrates, ADK still fluctuates between multiple functional states, reflecting an intrinsic capability of large-scale conformational fluctuations which may be essential to its biological function. The results based on the dual-ligands model provide the theoretical validation of random bisubstrate biproducts (Bi–Bi) mechanism for the enzymatic reaction of ADK. Additionally, the pathway flux analysis strongly suggests that the motion of the NMP domain is the rate-determining step for the conformational cycle (opening and closing).
Co-reporter:Han Yan;Lei Zhao;Liang Hu;Erkang Wang;Xidi Wang
PNAS 2013 Volume 110 (Issue 45 ) pp:E4185-E4194
Publication Date(Web):2013-11-05
DOI:10.1073/pnas.1310692110
The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out,
the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning
and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions
represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural
networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a
nonequilibrium landscape–flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential
landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and
oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only
by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric
connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring
attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations
on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye
movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape
topography against wirings, which are in good agreements with experiments.
Co-reporter:Yong Wang;Xiakun Chu;Sonia Longhi;Philippe Roche;Wei Han;Erkang Wang;
Proceedings of the National Academy of Sciences 2013 110(40) pp:E3743-E3752
Publication Date(Web):September 16, 2013
DOI:10.1073/pnas.1308381110
Numerous relatively short regions within intrinsically disordered proteins (IDPs) serve as molecular recognition elements
(MoREs). They fold into ordered structures upon binding to their partner molecules. Currently, there is still a lack of in-depth
understanding of how coupled binding and folding occurs in MoREs. Here, we quantified the unbound ensembles of the α-MoRE
within the intrinsically disordered C-terminal domain of the measles virus nucleoprotein. We developed a multiscaled approach
by combining a physics-based and an atomic hybrid model to decipher the mechanism by which the α-MoRE interacts with the X
domain of the measles virus phosphoprotein. Our multiscaled approach led to remarkable qualitative and quantitative agreements
between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly
interconverts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental
observations. We quantified the underlying global folding–binding landscape. This leads to a synergistic mechanism in which
the recognition event proceeds via (minor) conformational selection, followed by (major) induced folding. We also provided
evidence that the α-MoRE is a compact molten globule-like IDP and behaves as a downhill folder in the induced folding process.
We further provided a theoretical explanation for the inherent connections between “downhill folding,” “molten globule,” and
“intrinsic disorder” in IDP-related systems. Particularly, we proposed that binding and unbinding of IDPs proceed in a stepwise
way through a “kinetic divide-and-conquer” strategy that confers them high specificity without high affinity.
Co-reporter:Zaizhi Lai, Nicholas K. Preketes, Shaul Mukamel, and Jin Wang
The Journal of Physical Chemistry B 2013 Volume 117(Issue 16) pp:4661-4669
Publication Date(Web):February 28, 2013
DOI:10.1021/jp309122b
Protein folding is one of the most fundamental problems in modern molecular biology. Uncovering the detailed folding mechanism requires methods that can monitor the structures at high temporal and spatial resolution. Two-dimensional infrared (2DIR) spectroscopy is a new tool for studying protein structures and dynamics with high time resolution. Using atomistic molecular dynamics simulations, we illustrate the folding process of Trp-cage along the dominant pathway on the free energy landscape by analyzing nonchiral and chiral coherent 2DIR spectra along the pathway. Isotope labeling is used to reveal residue-specific information. We show that the high resolution structural sensitivity of 2DIR can differentiate the ensemble evolution of protein and thus provides a microscopic picture of the folding process.
Co-reporter:Xuan Yang;Linfeng Gan;Lei Han; Erkang Wang; Jin Wang
Angewandte Chemie International Edition 2013 Volume 52( Issue 7) pp:2022-2026
Publication Date(Web):
DOI:10.1002/anie.201205929
Co-reporter:Wei Wu and Jin Wang
The Journal of Physical Chemistry B 2013 Volume 117(Issue 42) pp:12908-12934
Publication Date(Web):July 18, 2013
DOI:10.1021/jp402064y
Spatially extended systems are widely encountered in physics, chemistry, and biology for studying many important natural phenomena. In this work, we established a landscape framework for studying general stochastic spatially extended systems with intrinsic statistical fluctuations that can be applied to both equilibrium systems with detailed balance and nonequilibrium systems without detailed balance. We set up the master equation for general stochastic spatially extended systems (functional master equation) from two fundamental dynamical ingredients that characterize the elementary state transitions of spatially extended systems. We explored the entire spectrum of the various approximations of the functional master equation under certain conditions, from the functional Kramers–Moyal equation to the functional Fokker–Planck equation and its equivalent, the functional Langevin equation, to the macroscopic deterministic equation. We uncovered the Lyapunov functionals which are required to quantify the global stability and function of the system for both the deterministic and stochastic spatially extended systems. The global potential landscape functional for stochastic spatially extended systems can be quantified by the steady state probability distribution functional. In the small fluctuation limit, the potential landscape functional becomes the Lyapunov functional for the corresponding deterministic spatially extended system. The relative entropy functional (or free energy functional) proves to be the Lyapunov functional for the stochastic spatially extended systems. The potential landscape functional and the relative entropy functional quantify the global stability and function of the deterministic and stochastic spatially extended systems for both equilibrium and nonequilibrium conditions. The chemical reaction–diffusion systems as a typical and important class of spatially extended systems is explored on its own terms as well as used as a direct application of the general framework to derive more specific results for reaction–diffusion systems. A biological system, the bicoid protein concentration distribution in fruit fly embryo development, which can be modeled as a specific type of reaction–diffusion dynamics, is studied using the proposed framework. We found both the bicoid concentration and its fluctuation decay from anterior to posterior when the source producing the bicoid protein is located at the anterior point. The corresponding local funneled landscape basin of the bicoid concentration becomes narrower and steeper from anterior to posterior in such a case.
Co-reporter:Jiangtao Ren; Jiahai Wang; Jin Wang; Erkang Wang
Chemistry - A European Journal 2013 Volume 19( Issue 2) pp:479-483
Publication Date(Web):
DOI:10.1002/chem.201202430
Co-reporter:Shanling Xu, Jiyang Liu, Tianshu Wang, Hailong Li, Yuqing Miao, Yaqing Liu, Jin Wang, Erkang Wang
Talanta 2013 Volume 104() pp:122-127
Publication Date(Web):30 January 2013
DOI:10.1016/j.talanta.2012.11.040
Developing non-invasive, sensitive and specific sensing strategies for cancerous cell detection with simple and low cost instrumentations provide great advantages in cancer research and early diagnosis of diseases. In the present work, gold nanoparticles (Au NPs) functionalized with recognition components (folic acid) and signal indicator (ferrocene) was designed to fabricate electrochemical cytosensor. The Au NPs can not only accelerate electron transfer between signal indicator and the underlying electrode but also accumulate more ferrocene on the cytosensor surface to magnify signal for improving detection sensitivity. The surface-tethered folic acid plays a key role in specific binding folate receptor-riched HeLa cells on the cytosensor surface, resulting in corresponding current signal change measured by differential pulse voltammetry method. A wide detection range from 10 to 106 cells/mL with a detection limit as low as 10 cells/mL for cancerous cells was reached in the presence of a large amount of normal ones with fast differential pulse voltammetry measurement. Detection of the captured cells can be finished within 1 min. The developed strategy provides a new way for operationally simple, rapid, sensitive and specific detection of cancerous cells.Highlights► A highly sensitive and selective cytosensor was developed. ► Surface-confined ferrocene was used as the current signal indicator. ► Gold nanoparticles play an important role in the signal magnification. ► The selective detection range of HeLa cell was from 10 to 106 cells/mL. ► Fast DPV measurement could reduce the loss of cell viability.
Co-reporter:Jiyang Liu, Yinan Qin, Dan Li, Tianshu Wang, Yaqing Liu, Jin Wang, Erkang Wang
Biosensors and Bioelectronics 2013 Volume 41() pp:436-441
Publication Date(Web):15 March 2013
DOI:10.1016/j.bios.2012.09.002
Electrochemical methods have attracted considerable attention for developing cytosensing system since they can decrease the cost and time requirement for cell detection with simple instrumentation. Herein, a label-free electrochemical cytosensor with surface-confined ferrocene as signal indicator was developed for highly sensitive and selective detection of cancer cell. With layer-by-layer (LBL) self-assembly technique, positively charged poly(ethylene imine) functionalized with ferrocene (Fc-PEI) and negatively charged single-wall carbon nanotubes (SWNTs) were alternately assembled on 3-mercaptopropionic acid (MPA) modified gold substrate. Folic acid (FA) was covalently bonded onto SWNTs surface to specifically recognize cancer cells according to the high affinity of FA for folate receptor (FR) on cellular surface. The developed cytosensor presented high sensitivity and selectivity for the detection of human cervical carcinoma (HeLa) cell. By using fast-response differential pulse voltammetry (DPV) method, a wide detection range from 10 to 106 cells/mL with a detection limit as low as 10 cells/mL was reached even in the presence of a large amount of non-cancerous cells.Highlights► A cytosensor with high sensitivity and selectivity was developed. ► Folic acid was used to specifically recognize cancer cells. ► Surface-confined ferrocene was used as the signal indicator. ► The detection concentration range of HeLa cell was from 10 to 106 cells/mL. ► Fast DPV measurement could reduce the loss of cell viability.
Co-reporter:Kun Zhang;Masaki Sasai
PNAS 2013 Volume 110 (Issue 37 ) pp:14930-14935
Publication Date(Web):2013-09-10
DOI:10.1073/pnas.1305604110
Physical and biological systems are often involved with coupled processes of different time scales. In the system with electronic
and atomic motions, for example, the interplay between the atomic motion along the same energy landscape and the electronic
hopping between different landscapes is critical: the system behavior largely depends on whether the intralandscape motion
is slower (adiabatic) or faster (nonadiabatic) than the interlandscape hopping. For general nonequilibrium dynamics where
Hamiltonian or energy function is unknown a priori, the challenge is how to extend the concepts of the intra- and interlandscape
dynamics. In this paper we establish a theoretical framework for describing global nonequilibrium and nonadiabatic complex
system dynamics by transforming the coupled landscapes into a single landscape but with additional dimensions. On this single
landscape, dynamics is driven by gradient of the potential landscape, which is closely related to the steady-state probability
distribution of the enlarged dimensions, and the probability flux, which has a curl nature. Through an example of a self-regulating
gene circuit, we show that the curl flux has dramatic effects on gene regulatory dynamics. The curl flux and landscape framework
developed here are easy to visualize and can be used to guide further investigation of physical and biological nonequilibrium
systems.
Co-reporter:Xiakun Chu;Erkang Wang;Linfeng Gan
PNAS 2013 Volume 110 (Issue 26 ) pp:E2342-E2351
Publication Date(Web):2013-06-25
DOI:10.1073/pnas.1220699110
Biomolecular functions are determined by their interactions with other molecules. Biomolecular recognition is often flexible
and associated with large conformational changes involving both binding and folding. However, the global and physical understanding
for the process is still challenging. Here, we quantified the intrinsic energy landscapes of flexible biomolecular recognition
in terms of binding–folding dynamics for 15 homodimers by exploring the underlying density of states, using a structure-based
model both with and without considering energetic roughness. By quantifying three individual effective intrinsic energy landscapes
(one for interfacial binding, two for monomeric folding), the association mechanisms for flexible recognition of 15 homodimers
can be classified into two-state cooperative “coupled binding–folding” and three-state noncooperative “folding prior to binding”
scenarios. We found that the association mechanism of flexible biomolecular recognition relies on the interplay between the
underlying effective intrinsic binding and folding energy landscapes. By quantifying the whole global intrinsic binding–folding
energy landscapes, we found strong correlations between the landscape topography measure Λ (dimensionless ratio of energy
gap versus roughness modulated by the configurational entropy) and the ratio of the thermodynamic stable temperature versus
trapping temperature, as well as between Λ and binding kinetics. Therefore, the global energy landscape topography determines
the binding–folding thermodynamics and kinetics, crucial for the feasibility and efficiency of realizing biomolecular function.
We also found “U-shape” temperature-dependent kinetic behavior and a dynamical cross-over temperature for dividing exponential
and nonexponential kinetics for two-state homodimers. Our study provides a unique way to bridge the gap between theory and
experiments.
Co-reporter:Zaizhi Lai, Nicholas K Preketes, Jun Jiang, Shaul Mukamel, and Jin Wang
The Journal of Physical Chemistry Letters 2013 Volume 4(Issue 11) pp:1913-1917
Publication Date(Web):May 20, 2013
DOI:10.1021/jz400598r
Probing the underlying free-energy landscape, pathway, and mechanism is the key to understanding protein folding in theory and experiment. Time-resolved two-dimensional infrared (2DIR) with femtosecond laser pulses has emerged as a powerful tool for investigating the protein folding dynamics on much faster time scales than possible by NMR. We have employed molecular dynamics simulations to compute 2DIR spectra of the folding process of a peptide, Beta3s. Simulated nonchiral and chiral 2DIR signals illustrate the variation of the spectra as the peptide conformation evolves along the free-energy landscape. Chiral spectra show stronger changes than the nonchiral signals because cross peaks caused by the formation of the β-sheet are clearly resolved. Chirality-induced 2DIR may be used to detect the folding of β-sheet proteins with high spectral and temporal resolution.Keywords: chiral signal; free-energy landscape; multidimensional spectroscopy; nonchiral signal; protein folding;
Co-reporter:Yong Wang ; Xiakun Chu ; Zucai Suo ; Erkang Wang
Journal of the American Chemical Society 2012 Volume 134(Issue 33) pp:13755-13764
Publication Date(Web):July 24, 2012
DOI:10.1021/ja3045663
Approximately three-fourths of eukaryotic proteins are composed of multiple independently folded domains. However, much of our understanding is based on single domain proteins or isolated domains whose studies directly lead to well-known energy landscape theory in which proteins fold by navigating through a funneled energy landscape toward native structure ensembles. The degrees of freedom for proteins with multiple domains are many orders of magnitude larger than that for single domain proteins. Now, the question arises: How do the multidomain proteins solve the “protein folding problem”? Here, we specifically address this issue by exploring the structure folding relationship of Sulfolobus solfataricus DNA polymerase IV (DPO4), a prototype Y-family DNA polymerase which contains a polymerase core consisting of a palm (P domain), a finger (F domain), and a thumb domain (T domain) in addition to a little finger domain (LF domain). The theoretical results are in good agreement with the experimental data and lead to several theoretical predictions. Finally, we propose that for rapid folding into well-defined conformations which carry out the biological functions, four-domain DPO4 employs a divide-and-conquer strategy, that is, combining multiple individual folding funnels into a single funnel (domains fold independently and then coalesce). In this way, the degrees of freedom for multidomain proteins are polynomial rather than exponential, and the conformational search process can be reduced effectively from a large to a smaller time scale.
Co-reporter:Chunhe Li, Erkang Wang, and Jin Wang
ACS Synthetic Biology 2012 Volume 1(Issue 6) pp:229
Publication Date(Web):May 4, 2012
DOI:10.1021/sb300020f
Metabolic networks have gained broad attention in recent years as a result of their important roles in biological systems. However, how to quantify the global stability of the metabolic networks is still challenging. We develop a probabilistic landscape approach to investigate the global natures of the metabolic system under external fluctuations. As an example, we choose a model of the carbohydrate metabolism and the anaplerotic synthesis of oxalacetate in Aspergillus niger under conditions of citric acid accumulation to explore landscape topography. The landscape has a funnel shape, which guarantees the robustness of system under fluctuations and perturbations. Robustness ratio (RR), defined as the ratio of gap between lowest potential and average potential versus roughness measured by the dispersion or square root of variations of potentials, can be used to quantitatively evaluate the global stability of metabolic networks, and the larger the RR value, the more stable the system. Results of the entropy production rate imply that nature might evolve such that the network is robust against perturbations from environment or network wirings and performs specific biological functions with less dissipation cost. We also carried out a sensitivity analysis of parameters and uncovered some key network structure factors such as kinetic rates or wirings connecting the protein species nodes, which influence the global natures of the system. We found there is a strong correlation between the landscape topography and the input-output response. The more stable and robust the metabolic network is, the sharper the response is.Keywords: fluctuations; global stability; metabolic network; probabilistic landscape; robustness ratio;
Co-reporter:Jiangtao Ren, Jiahai Wang, Jin Wang, Nathan W. Luedtke, Erkang Wang
Biosensors and Bioelectronics 2012 Volume 35(Issue 1) pp:401-406
Publication Date(Web):15 May 2012
DOI:10.1016/j.bios.2012.03.028
In this work, a simple and label-free fluorescent method via fluorescent indicator displacement (FID) was proposed for enantioselectively determining d-enantiomer of arginine vasopressin (DV) using DV-specific DNA aptamer (V-apt) and one guanidiniophthalocyanine dye (Zn-DIGP). Zn-DIGP that preferentially binds to single-stranded DNA with fluorescence enhancement rather than duplexes occupies the long internal loop of V-apt and generates intensive fluorescence. Then DV is introduced into the solution containing Zn-DIGP and V-apt, and displaces the Zn-DIGP from the binding site of internal loop, leading to fluorescence decrease. But l-enantiomer cannot induce any fluorescence change due to the selectivity of V-apt. This established FID technique can detect DV with a detection limit of 100 nM and exhibits a broad linear range, and is able to discriminate enantiomers of arginine vasopressin unambiguously. Moreover chiral separation by chromatography, complicated experimental procedures and covalent modification of tags (such as organic dyes, redox-active metal complexes) are avoided in our strategy. This simple and label-free method is promising for fabricating diverse aptasensors to determine other biomolecules and drugs.Highlights► Enantioselectively detection of d-oligopeptide was realized by fluorescent method. ► d-Enantiomer-specific DNA aptamer was utilized as the chiral selector. ► The mechanism is based on fluorescent indicator displacement (FID). ► The FID method is label-free, very simple and cost-effective.
Co-reporter:Wei Hong;Dr. Yan Du;Tianshu Wang;Jiyang Liu;Dr. Yaqing Liu; Jin Wang; Erkang Wang
Chemistry - A European Journal 2012 Volume 18( Issue 47) pp:14939-14942
Publication Date(Web):
DOI:10.1002/chem.201203286
Co-reporter:Jiangtao Ren, Jiahai Wang, Jin Wang, Nathan W. Luedtke, Erkang Wang
Biosensors and Bioelectronics 2012 Volume 31(Issue 1) pp:316-322
Publication Date(Web):15 January 2012
DOI:10.1016/j.bios.2011.10.038
In recent years, bioanalytical technology based on G-quadruplex has been paid significant attention due to its versatility and stimulus-responsive reconfiguration. Notwithstanding, several key issues for template-directed reassembly of G-quadruplex have not been resolved: what is the key factor for determining the sensitivity and selectivity of split G-quadruplex probes toward target DNA. Therefore, in this study, we designed three pairs of split G-quadruplex probes and investigated the sensitivity and selectivity of these systems in terms of potassium ion concentration and split modes of G-quadruplex. Due to its simplicity and sensitivity, N-methyl-mesoporphyrin (NMM) as fluorescence probes was used to monitor the target-directed reassembling process of G-quadruplex. A G-quadruplex sequence derived from the c-Myc promoter was split into “symmetric” probes, where each fragment contained two runs of guanine residues (2 + 2), or into “asymmetric” fragments each containing (3 + 1 or 1 + 3) runs of guanine residues. In all three cases, the sensitivity of target detection was highly dependent on the thermodynamic stability of the hybrid structure, which can be modulated by potassium ion concentrations. Using a combination of CD, fluorescence, and UV spectroscopy, we found that increasing potassium concentrations can increase the sensitivity of target detection, but can decrease the selectivity of discriminating cognate versus mismatched “target” DNA. The previous argument that asymmetrically split probes were always better than symmetrically split probes in terms of selectivity was not plausible anymore. These results demonstrate how the sensitivities and selectivity of split probes to mutations can be optimized by tuning the thermodynamic stability of the three-way junction complex.Highlights► Three split probe designs of G-quadruplex using fluorescence were studied. ► Potassium ion is critical in the stability of hybrids of split probes and target DNA. ► The stability of hybrid decides the sensitivity and selectivity of each design. ► Symmetrically split G-quadruplex is more favorable for single mismatch discrimination.
Co-reporter:Jin Wang;Ronaldo J. Oliveira;Xiakun Chu;Paul C. Whitford;Jorge Chahine;Wei Han;Erkang Wang;José N. Onuchic;Vitor B.P. Leite
PNAS 2012 Volume 109 (Issue 39 ) pp:
Publication Date(Web):2012-09-25
DOI:10.1073/pnas.1212842109
The energy landscape approach has played a fundamental role in advancing our understanding of protein folding. Here, we quantify
protein folding energy landscapes by exploring the underlying density of states. We identify three quantities essential for
characterizing landscape topography: the stabilizing energy gap between the native and nonnative ensembles δE, the energetic roughness ΔE, and the scale of landscape measured by the entropy S. We show that the dimensionless ratio between the gap, roughness, and entropy of the system accurately predicts the thermodynamics, as well as the kinetics of folding. Large Λ implies that the energy gap (or landscape
slope towards the native state) is dominant, leading to more funneled landscapes. We investigate the role of topological and
energetic roughness for proteins of different sizes and for proteins of the same size, but with different structural topologies.
The landscape topography ratio Λ is shown to be monotonically correlated with the thermodynamic stability against trapping,
as characterized by the ratio of folding temperature versus trapping temperature. Furthermore, Λ also monotonically correlates
with the folding kinetic rates. These results provide the quantitative bridge between the landscape topography and experimental
folding measurements.
Co-reporter:Weixin Xu, Zaizhi Lai, Ronaldo J. Oliveira, Vitor B. P. Leite, and Jin Wang
The Journal of Physical Chemistry B 2012 Volume 116(Issue 17) pp:5152-5159
Publication Date(Web):April 12, 2012
DOI:10.1021/jp212132v
Configuration-dependent diffusion (CDD) is important for protein folding kinetics with small thermodynamic barriers. CDD can be even more crucial in downhill folding without thermodynamic barriers. We explored the CDD of a downhill protein (BBL), and a two-state protein (CI2). The hidden kinetic barriers due to CDD were revealed. The increased ∼1 kBT kinetic barrier is in line with experimental value based on other fast folding proteins. Compared to that of CI2, the effective free-energy profile of BBL is found to be significantly influenced by CDD, and the kinetics are totally determined by diffusion. These findings are consistent with both earlier bulk and single-molecule fluorescence measurements. In addition, we found the temperature dependence of CDD. We also found that the ratio of folding transition temperature against optimal kinetic folding temperature can provide both a quantitative measure for the underlying landscape topography and an indicator for the possible appearance of downhill folding. Our study can help for a better understanding of the role of diffusion in protein folding dynamics.
Co-reporter:Jiangtao Ren, Jiahai Wang, Lei Han, Erkang Wang and Jin Wang
Chemical Communications 2011 vol. 47(Issue 38) pp:10563-10565
Publication Date(Web):22 Aug 2011
DOI:10.1039/C1CC13973H
Kinetically grafting G-quadruplexes onto one-dimensional DNA nanostructures with precise positioning was realized in this study. The programs hold great promise for label-free and enzyme-free detection of various targets as a result of signal amplification from G-quadruplexes, and building DNA nanostructures as scaffolds due to the molecular recognition capacity of G-quadruplex aptamers.
Co-reporter:Chunhe Li, Erkang Wang, Jin Wang
Chemical Physics Letters 2011 Volume 505(1–3) pp:75-80
Publication Date(Web):21 March 2011
DOI:10.1016/j.cplett.2011.02.020
Abstract
We develop a theoretical framework for exploring global natures of non-equilibrium dynamical systems under intrinsic statistical fluctuations. We found the underlying driving force can be decomposed into three terms: gradient of potential landscape, curl probability flux, inhomogeneity of diffusion. We studied a limit cycle oscillation model and found that the potential landscape has a Mexican hat close ring valley shape and attracts the system down to the ring while the curl probability flux on the ring drives the coherent oscillation. The barrier heights characterizing the landscape topography provide a quantitative measure for global stability of non-equilibrium dynamical systems.
Co-reporter:Qiang Lu, Nicolas Nassar, Jin Wang
Chemical Physics Letters 2011 Volume 516(4–6) pp:233-238
Publication Date(Web):18 November 2011
DOI:10.1016/j.cplett.2011.09.071
Abstract
The hydrolysis by Ras plays pivotal roles in the activation of signaling pathways that lead to cell growth, proliferation, and differentiation. Despite their significant role in human cancer, the hydrolysis mechanism remains unclear. In the present Letter, we propose a GTP hydrolysis mechanism in which the γ phosphate is cut off primarily by magnesium ion. We studied both normal and mutated Ras and the cause of the malfunction of these mutants, compared the effect of Mg2+ and Mn2+. The simulation results are consistent with the experiments and support the new hydrolysis mechanism. This work will benefit both GTPases and ATPases hydrolysis studies.
Co-reporter:Haidong Feng, Jin Wang
Chemical Physics Letters 2011 Volume 501(4–6) pp:562-566
Publication Date(Web):7 January 2011
DOI:10.1016/j.cplett.2010.11.017
Co-reporter:Jiangtao Ren;Haixia Qin;Jiahai Wang
Analytical and Bioanalytical Chemistry 2011 Volume 399( Issue 8) pp:2763-2770
Publication Date(Web):2011 March
DOI:10.1007/s00216-011-4669-0
In this study we have used two fluorescent probes, tetrakis(diisopropylguanidino)-zinc-phthalocyanine (Zn-DIGP) and N-methylmesoporphyrin IX (NMM), to monitor the reassembly of “split” G-quadruplex probes on hybridization with an arbitrary “target” DNA. According to this approach, each split probe is designed to contain half of a G-quadruplex-forming sequence fused to a variable sequence that is complementary to the target DNA. Upon mixing the individual components, both base-pairing interactions and G-quadruplex fragment reassembly result in a duplex–quadruplex three-way junction that can bind to fluorescent dyes in a G-quadruplex-specific way. The overall fluorescence intensities of the resulting complexes were dependent on the formation of proper base-pairing interactions in the duplex regions, and on the exact identity of the fluorescent probe. Compared with samples lacking any “target” DNA, the fluorescence intensities of Zn-DIGP-containing samples were lower, and the fluorescence intensities of NMM-containing samples were higher on addition of the target DNA. The resulting biosensors based on Zn-DIGP are therefore termed “turn-off” whereas the biosensors containing NMM are defined as “turn-on”. Both of these biosensors can detect target DNAs with a limit of detection in the nanomolar range, and can discriminate mismatched from perfectly matched target DNAs. In contrast with previous biosensors based on the peroxidase activity of heme-bound split G-quadruplex probes, the use of fluorescent dyes eliminates the need for unstable sensing components (H2O2, hemin, and ABTS). Our approach is direct, easy to conduct, and fully compatible with the detection of specific DNA sequences in biological fluids. Having two different types of probe was highly valuable in the context of applied studies, because Zn-DIGP was found to be compatible with samples containing both serum and urine whereas NMM was compatible with urine, but not with serum-containing samples.
Co-reporter:Haidong Feng, Jin Wang
Chemical Physics Letters 2011 510(4–6) pp: 267-272
Publication Date(Web):
DOI:10.1016/j.cplett.2011.05.041
Co-reporter:Jin Wang;Erkang Wang;Kun Zhang;Li Xu
PNAS 2011 Volume 108 (Issue 20 ) pp:8257-8262
Publication Date(Web):2011-05-17
DOI:10.1073/pnas.1017017108
We developed a theoretical framework to prove the existence and quantify the Waddington landscape as well as chreode-biological
paths for development and differentiation. The cells can have states with the higher probability ones giving the different
cell types. Different cell types correspond to different basins of attractions of the probability landscape. We study how
the cells develop from undifferentiated cells to differentiated cells from landscape perspectives. We quantified the Waddington
landscape through construction of underlying probability landscape for cell development. We show the developmental process
proceeds as moving from undifferentiated to the differentiated basins of attractions. The barrier height of the basins of
attractions correlates with the escape time that determines the stability of cell types. We show that the developmental process
can be quantitatively described and uncovered by the biological paths on the quantified Waddington landscape from undifferentiated
to the differentiated cells. We found the dynamics of the developmental process is controlled by a combination of the gradient
and curl force on the landscape. The biological paths often do not follow the steepest descent path on the landscape. The
landscape framework also quantifies the possibility of reverse differentiation process such as cell reprogramming from differentiated
cells back to the original stem cell. We show that the biological path of reverse differentiation is irreversible and different
from the one for differentiation process. We found that the developmental process described by the underlying landscape and
the associated biological paths is relatively stable and robust against the influences of environmental perturbations.
Co-reporter:Haidong Feng, Bo Han, and Jin Wang
The Journal of Physical Chemistry B 2011 Volume 115(Issue 5) pp:1254-1261
Publication Date(Web):December 28, 2010
DOI:10.1021/jp109036y
We explore the stochastic dynamics of self-regulative genes from fluctuations of molecular numbers and of on and off switching of gene states due to regulatory protein binding/unbinding to the genes. We found when the binding/unbinding is relatively fast (slow) compared with the synthesis/degradation of proteins in adiabatic (nonadiabatic) case the self-regulators can exhibit one or two peak (two peak) distributions in protein concentrations. This phenomena can also be quantified through Fano factors. This shows that even with the same architecture (topology of wiring) networks can have quite different functions (phenotypes), consistent with recent single molecule single gene experiments. We further found the inhibition and activation curves to be consistent with previous results (monomer binding) in adiabatic regime, but, in nonadiabatic regimes, show significantly different behaviors with previous predictions (monomer binding). Such difference is due to the slow (nonadiabatic) dimer binding/unbinding effect, and it has never been reported before. We derived the nonequilibrium phase diagrams of monostability and bistability in adiabatic and nonadiabatic regimes. We studied the dynamical trajectories of the self-regulating genes on the underlying landscapes from nonadiabatic to adiabatic limit, and we provide a global picture of understanding and show an analogy to the electron transfer problem. We studied the stability and robustness of the systems through mean first passage time (MFPT) from one peak (basin of attraction) to another and found both monotonic and nonmonotonic turnover behavior from adiabatic to nonadiabatic regimes. For the first time, we explore global dissipation by entropy production and the relation with binding/unbinding processes. Our theoretical predictions for steady state peaks, fano factos, inhibition/activation curves, and MFPT can be probed and tested from experiments.
Co-reporter:Zai-Zhi Lai, Qiang Lu, and Jin Wang
The Journal of Physical Chemistry B 2011 Volume 115(Issue 14) pp:4147-4159
Publication Date(Web):March 22, 2011
DOI:10.1021/jp110845u
Functional conformational transition in the glutamine-binding protein (GlnBP) is known to be the key to bind and transfer ligand glutamine. Here, we developed a structure-based double-well model to investigate the thermodynamic and kinetic natures of the GlnBP conformational transition. We uncovered the underlying free-energy landscape of the conformational transition with different temperatures. The analysis shows that below the melting temperature, two basins of attractions emerge, corresponding to the open state and the closed state of the protein. We explored the kinetic property of the conformational switch through the mean and distribution of the first passage time as well as the autocorrelation function. The kinetics implies the complexity and the hierarchical structure of the underlying energy landscape. We built the contact maps of the structures to probe the structural evolution of the conformational transition. Finally, the ϕ values of the residues were calculated to identify the important residues (hot spots) of the transition state.
Co-reporter:Jin Wang;Chunhe Li;Erkang Wang
PNAS 2010 Volume 107 (Issue 18 ) pp:8195-8200
Publication Date(Web):2010-05-04
DOI:10.1073/pnas.0910331107
Studying the cell cycle process is crucial for understanding cell growth, proliferation, development, and death. We uncovered
some key factors in determining the global robustness and function of the budding yeast cell cycle by exploring the underlying
landscape and flux of this nonequilibrium network. The dynamics of the system is determined by both the landscape which attracts
the system down to the oscillation orbit and the curl flux which drives the periodic motion on the ring. This global structure
of landscape is crucial for the coherent cell cycle dynamics and function. The topography of the underlying landscape, specifically
the barrier height separating basins of attractions, characterizes the capability of changing from one part of the system
to another. This quantifies the stability and robustness of the system. We studied how barrier height is influenced by environmental
fluctuations and perturbations on specific wirings of the cell cycle network. When the fluctuations increase, the barrier
height decreases and the period and amplitude of cell cycle oscillation is more dispersed and less coherent. The corresponding
dissipation of the system quantitatively measured by the entropy production rate increases. This implies that the system is
less stable under fluctuations. We identified some key structural elements for wirings of the cell cycle network responsible
for the change of the barrier height and therefore the global stability of the system through the sensitivity analysis. The
results are in agreement with recent experiments and also provide new predictions.
Co-reporter:David Lepzelter, Haidong Feng, Jin Wang
Chemical Physics Letters 2010 490(4–6) pp: 216-220
Publication Date(Web):
DOI:10.1016/j.cplett.2010.03.029
Co-reporter:Ming Zhou;Xiliang Zheng ;Shaojun Dong
Chemistry - A European Journal 2010 Volume 16( Issue 26) pp:7719-7724
Publication Date(Web):
DOI:10.1002/chem.201000619
Co-reporter:Haidong Feng, Bo Han and Jin Wang
The Journal of Physical Chemistry Letters 2010 Volume 1(Issue 12) pp:1836-1840
Publication Date(Web):May 28, 2010
DOI:10.1021/jz100484p
We developed a new method for quantifying the paths and the associated weights for complex systems in discrete state space with general Markov chains. We identified the dominant paths among all possible paths. We applied our method to gene networks. We computed the dominant paths and the transition rates from the “off” basin to the “on” basin for the gene regulatory motif, self-activators, and observe turnover kinetic behavior of transitions from nonadiabatic to adiabatic regimes.Keywords: gene networks; Markov chains;
Co-reporter:Zuojia Liu, Jin Wang and Erkang Wang
The Journal of Physical Chemistry B 2010 Volume 114(Issue 1) pp:638-642
Publication Date(Web):December 10, 2009
DOI:10.1021/jp909017j
The molecular analysis of thymopentin (TP5)/class II major histocompatibility complex (MHC II) complexes has been basically understood; however, the mechanism by which TP5-MHC II complexes are formed is largely unexplored. Compared with Epstein−Barr virus (EBV)-transformed B cells expressing human leucocyte antigen DR (HLA-DR), no fluorescent signal was observed on the DR-deficient cell line. This indicates that FITC labeled TP5 (FITC-TP5) is genuinely bound to HLA-DR. The binding specificity was confirmed by incubating FITC-TP5 with unlabeled TP5 and HA peptide as well as mAb for DR molecules. In addition, the binding appeared to be rapid in living antigen-presenting cell (APC), which implies that TP5 is demonstrated on APC surface and does not require processing before associating with DR. Additional support for this surface binding arises from the observation that pretreatment of cells with a variety of metabolic inhibitors failed to decrease the level of TP5/DR complexes. However, temperature has an effect on the rate of binding between TP5 and DR molecules, which is well consistent with the qualitative predication of transition state theory. The formation of antigenic complexes is accelerated at acidic pH, which shows that the formation of TP5/DR complexes is a pH-dependent process.
Co-reporter:Dan Li, Gaiping Li, Peicai Li, Lixue Zhang, Zuojia Liu, Jin Wang, Erkang Wang
Biomaterials 2010 31(7) pp: 1850-1857
Publication Date(Web):
DOI:10.1016/j.biomaterials.2009.11.027
Co-reporter:Lijian Huang, Yueming Zhai, Shaojun Dong, Jin Wang
Journal of Colloid and Interface Science 2009 Volume 331(Issue 2) pp:384-388
Publication Date(Web):15 March 2009
DOI:10.1016/j.jcis.2008.12.008
In the paper, we report an efficient method to prepare high yield (up to 97%) of silver nanoplates. Synthesis of silver nanoplates was carried out in a binary solvent system of N,NN,N-dimethylformamide (DMF) and toluene, in which DMF served as the reductant and polyvinylpyrrolidone (PVP) as the capping agent. By increasing the ratio of toluene to DMF to 7:6, silver nanoplates can be successfully synthesized; otherwise other shaped nanoparticles would be the major products. The nanoplate sample was characterized by TEM, HRTEM, SAED, XRD, AFM and UV–visible spectroscopy, proving the high nanoplate purity of this sample. The influence of toluene content, other solvents, AgNO3 concentration, preparation temperature and chloride ions was also examined, which suggests that the function of non-polar solvents in this system is to enhance the PVP coverage on silver surface and, furthermore, to facilitate the preferential adsorption of PVP on two (111) facets of silver nanoplates.TEM image and XRD pattern of a Ag nanoplate sample prepared by adding toluene as the co-solvent.
Co-reporter:Qiang Lu and Jin Wang
The Journal of Physical Chemistry B 2009 Volume 113(Issue 5) pp:1517-1521
Publication Date(Web):January 13, 2009
DOI:10.1021/jp808923a
We developed a coarse-grained yet microscopic detailed model to study the statistical fluctuations of single-molecule protein conformational dynamics of adenylate kinase. We explored the underlying conformational energy landscape and found that the system has two basins of attractions, open and closed conformations connected by two separate pathways. The kinetics is found to be nonexponential, consistent with single- molecule conformational dynamics experiments. Furthermore, we found that the statistical distribution of the kinetic times for the conformational transition has a long power law tail, reflecting the exponential density of state of the underlying landscape. We also studied the joint distribution of the two pathways and found memory effects.
Co-reporter:Jin Wang;Chunhe Li;Erkang Wang;Xidi Wang
PNAS 2009 Volume 106 (Issue 10 ) pp:3752-3757
Publication Date(Web):2009-03-10
DOI:10.1073/pnas.0806427106
Identifying protein–protein interactions is crucial for understanding cellular functions. Genomic data provides opportunities
and challenges in identifying these interactions. We uncover the rules for predicting protein–protein interactions using a
frequent pattern tree (FPT) approach modified to generate a minimum set of rules (mFPT), with rule attributes constructed
from the interaction features of the yeast genomic data. The mFPT prediction accuracy is benchmarked against other commonly
used methods such as Bayesian networks and logistic regressions under various statistical measures. Our study indicates that
mFPT outranks other methods in predicting the protein–protein interactions for the database used. We predict a new protein–protein
interaction complex whose biological function is related to premRNA splicing and new protein–protein interactions within existing
complexes based on the rules generated. Our method is general and can be used to discover the underlying rules for protein–protein
interactions, genomic interactions, structure-function relationships, and other fields of research.
Co-reporter:Jin Wang, Li Xu, Kang Xue, Erkang Wang
Chemical Physics Letters 2008 Volume 463(4–6) pp:405-409
Publication Date(Web):1 October 2008
DOI:10.1016/j.cplett.2008.08.081
Abstract
We explored the origin of power law distribution observed in single-molecule conformational dynamics experiments. By establishing a kinetic master equation approach to study statistically the microscopic state dynamics, we show that the underlying landscape with exponentially distributed density of states leads to power law distribution of kinetics. The exponential density of states emerges when the system becomes glassy and landscape becomes rough with significant trapping. We predicted the power law decay coefficient is monotonically dependent on temperature which can be tested from ongoing experiments. This work bridges statistics from single-molecule kinetic experiments and topography of conformational energy landscape.
Co-reporter:Li Xu;Erkang Wang
PNAS 2008 Volume 105 (Issue 34 ) pp:12271-12276
Publication Date(Web):2008-08-26
DOI:10.1073/pnas.0800579105
We established a theoretical framework for studying nonequilibrium networks with two distinct natures essential for characterizing
the global probabilistic dynamics: the underlying potential landscape and the corresponding curl flux. We applied the idea
to a biochemical oscillation network and found that the underlying potential landscape for the oscillation limit cycle has
a distinct closed ring valley (Mexican hat-like) shape when the fluctuations are small. This global landscape structure leads
to attractions of the system to the ring valley. On the ring, we found that the nonequilibrium flux is the driving force for
oscillations. Therefore, both structured landscape and flux are needed to guarantee a robust oscillating network. The barrier
height separating the oscillation ring and other areas derived from the landscape topography is shown to be correlated with
the escaping time from the limit cycle attractor and provides a quantitative measure of the robustness for the network. The
landscape becomes shallower and the closed ring valley shape structure becomes weaker (lower barrier height) with larger fluctuations.
We observe that the period and the amplitude of the oscillations are more dispersed and oscillations become less coherent
when the fluctuations increase. We also found that the entropy production of the whole network, characterizing the dissipation
costs from the combined effects of both landscapes and fluxes, decreases when the fluctuations decrease. Therefore, less dissipation
leads to more robust networks. Our approach is quite general and applicable to other networks, dynamical systems, and biological
evolution. It can help in designing robust networks.
Co-reporter:Bo Han;Saul Lapidus
PNAS 2008 Volume 105 (Issue 16 ) pp:6039-6044
Publication Date(Web):2008-04-22
DOI:10.1073/pnas.0708708105
We develop a probabilistic method for analyzing global features of a cellular network under intrinsic statistical fluctuations,
which is important when there are finite numbers of molecules. By making a self-consistent mean field approximation of splitting
the variables in order to reduce the large number of degrees of freedom, which is reasonable for a not very strongly interacting
network, we discovered that the underlying energy landscape of the mitogen-activated protein kinases (MAPKs) signal transduction
network (with experimentally measured or inferred parameters such as chemical reaction rate coefficients in the network) is
funneled toward a global minimum characterized by the nonequilibrium steady-state fixed point of the system at the end of
the signal transduction process. For this system, we also show that the energy landscape is robust against intrinsic fluctuations
and random perturbation to the inherent chemical reaction rates. The ratio of the slope versus the roughness of the energy
landscape becomes a quantitative measure of robustness and stability of the network. Furthermore, we quantify the dissipation
cost of this nonequilibrium system through entropy production, caused by the nonequilibrium flux in the system. We found that
a lower dissipation cost corresponds to a more robust network. This least dissipation property might provide a design principle
for robust and functional networks. Finally, we find the possibility of bistable and oscillatory-like solutions, which are
important for cell fate decisions, upon perturbations. The method described here can be used in a variety of biological networks.
Co-reporter:Ronaldo J. Oliveira;Vitor B. P. Leite;Jorge Chahine
PNAS 2007 Volume 104 (Issue 37 ) pp:14646-14651
Publication Date(Web):2007-09-11
DOI:10.1073/pnas.0606506104
We show that diffusion can play an important role in protein-folding kinetics. We explicitly calculate the diffusion coefficient
of protein folding in a lattice model. We found that diffusion typically is configuration- or reaction coordinate-dependent.
The diffusion coefficient is found to be decreasing with respect to the progression of folding toward the native state, which
is caused by the collapse to a compact state constraining the configurational space for exploration. The configuration- or
position-dependent diffusion coefficient has a significant contribution to the kinetics in addition to the thermodynamic free-energy
barrier. It effectively changes (increases in this case) the kinetic barrier height as well as the position of the corresponding
transition state and therefore modifies the folding kinetic rates as well as the kinetic routes. The resulting folding time,
by considering both kinetic diffusion and the thermodynamic folding free-energy profile, thus is slower than the estimation
from the thermodynamic free-energy barrier with constant diffusion but is consistent with the results from kinetic simulations.
The configuration- or coordinate-dependent diffusion is especially important with respect to fast folding, when there is a
small or no free-energy barrier and kinetics is controlled by diffusion. Including the configurational dependence will challenge
the transition state theory of protein folding. The classical transition state theory will have to be modified to be consistent.
The more detailed folding mechanistic studies involving phi value analysis based on the classical transition state theory
also will have to be modified quantitatively.
Co-reporter:Jin Wang, Chilun Lee, George Stell
Chemical Physics 2005 Volume 316(1–3) pp:53-60
Publication Date(Web):19 September 2005
DOI:10.1016/j.chemphys.2005.04.045
Abstract
We study the effects of cooperative forces on protein folding kinetics using statistical energy landscape theory. We find that the mean first passage time for folding changes the shape from V to U-like curve dependence on the temperature when the effects of the cooperative forces are important, which is consistent with kinetic experiments. This supports the necessity for cooperative force. In addition, we find that cooperative forces tend to increase the free energy barrier so the kinetics is in general slower. Furthermore, we find that cooperative forces tend to suppress the fluctuations in kinetics more than non-cooperative forces. The cooperativity causes to the protein folding kinetics to be more two state-like.
Co-reporter:Ronaldo J. Oliveira, Paul C. Whitford, Jorge Chahine, Vitor B.P. Leite, Jin Wang
Methods (September 2010) Volume 52(Issue 1) pp:91-98
Publication Date(Web):1 September 2010
DOI:10.1016/j.ymeth.2010.04.016
We developed both analytical and simulation methods to explore the diffusion dynamics in protein folding. We found the diffusion as a quantitative measure of escape from local traps along the protein folding funnel with chosen reaction coordinates has two remarkable effects on kinetics. At a fixed coordinate, local escape time depends on the distribution of barriers around it, therefore the diffusion is often time distributed. On the other hand, the environments (local escape barriers) change along the coordinates, therefore diffusion is coordinate dependent. The effects of time-dependent diffusion on folding can lead to non-exponential kinetics and non-Poisson statistics of folding time distribution. The effects of coordinate dependent diffusion on folding can lead to the change of the kinetic barrier height as well as the position of the corresponding transition state and therefore modify the folding kinetic rates as well as the kinetic routes. Our analytical models for folding are based on a generalized Fokker–Planck diffusion equation with diffusion coefficient both dependent on coordinate and time. Our simulation for folding are based on structure-based folding models with a specific fast folding protein CspTm studied experimentally on diffusion and folding with single molecules. The coordinate and time-dependent diffusion are especially important to be considered in fast folding and single molecule studies, when there is a small or no free energy barrier and kinetics is controlled by diffusion while underlying statistics of kinetics become important. Including the coordinate dependence of diffusion will challenge the transition state theory of protein folding. The classical transition state theory will have to be modified to be consistent. The more detailed folding mechanistic studies involving phi value analysis based on the classical transition state theory will also have to be quantitatively modified. Complex kinetics with multiple time scales may allow us not only to explore the folding kinetics but also probe the local landscape and barrier height distribution with single-molecule experiments.
Co-reporter:Haidong Feng, Bo Han, Jin Wang
Biophysical Journal (7 March 2012) Volume 102(Issue 5) pp:
Publication Date(Web):7 March 2012
DOI:10.1016/j.bpj.2012.02.002
We quantify the potential landscape to determine the global stability and coherence of biological oscillations. We explore a gene network motif in our experimental synthetic biology studies of two genes that mutually repress and activate each other with self-activation and self-repression. We find that in addition to intrinsic molecular number fluctuations, there is another type of fluctuation crucial for biological function: the fluctuation due to the slow binding/unbinding of protein regulators to gene promoters. We find that coherent limit cycle oscillations emerge in two regimes: an adiabatic regime with fast binding/unbinding and a nonadiabatic regime with slow binding/unbinding relative to protein synthesis/degradation. This leads to two mechanisms of producing the stable oscillations: the effective interactions from averaging the gene states in the adiabatic regime; and the time delays due to slow binding/unbinding to promoters in the nonadiabatic regime, which can be tested by forthcoming experiments. In both regimes, the landscape has a topological shape of the Mexican hat in protein concentrations that quantitatively determines the global stability of limit cycle dynamics. The oscillation coherence is shown to be correlated with the shape of the Mexican hat characterized by the height from the oscillation ring to the central top. The oscillation period can be tuned in a wide range by changing the binding/unbinding rate without changing the amplitude much, which is important for the functionality of a biological clock. A negative feedback loop with time delays due to slow binding/unbinding can also generate oscillations. Although positive feedback is not necessary for generating oscillations, it can make the oscillations more robust.
Co-reporter:Jin Wang, Li Xu, Erkang Wang, Sui Huang
Biophysical Journal (7 July 2010) Volume 99(Issue 1) pp:
Publication Date(Web):7 July 2010
DOI:10.1016/j.bpj.2010.03.058
Differentiation from a multipotent stem or progenitor state to a mature cell is an essentially irreversible process. The associated changes in gene expression patterns exhibit time-directionality. This “arrow of time” in the collective change of gene expression across multiple stable gene expression patterns (attractors) is not explained by the regulated activation, the suppression of individual genes which are bidirectional molecular processes, or by the standard dynamical models of the underlying gene circuit which only account for local stability of attractors. To capture the global dynamics of this nonequilibrium system and gain insight in the time-asymmetry of state transitions, we computed the quasipotential landscape of the stochastic dynamics of a canonical gene circuit that governs branching cell fate commitment. The potential landscape reveals the global dynamics and permits the calculation of potential barriers between cell phenotypes imposed by the circuit architecture. The generic asymmetry of barrier heights indicates that the transition from the uncommitted multipotent state to differentiated states is inherently unidirectional. The model agrees with observations and predicts the extreme conditions for reprogramming cells back to the undifferentiated state.
Co-reporter:Chunhe Li, Erkang Wang, Jin Wang
Biophysical Journal (21 September 2011) Volume 101(Issue 6) pp:
Publication Date(Web):21 September 2011
DOI:10.1016/j.bpj.2011.08.012
Circadian rhythms with a period of ∼24 h, are natural timing machines. They are broadly distributed in living organisms, such as Neurospora, Drosophila, and mammals. The underlying natures of the rhythmic behavior have been explored by experimental and theoretical approaches. However, the global and physical natures of the oscillation under fluctuations are still not very clear. We developed a landscape and flux framework to explore the global stability and robustness of a circadian oscillation system. The potential landscape of the network is uncovered and has a global Mexican-hat shape. The height of the Mexican-hat provides a quantitative measure to evaluate the robustness and coherence of the oscillation. We found that in nonequilibrium dynamic systems, not only the potential landscape but also the probability flux are important to the dynamics of the system under intrinsic noise. Landscape attracts the systems down to the oscillation ring while flux drives the coherent oscillation on the ring. We also investigated the phase coherence and the entropy production rate of the system at different fluctuations and found that dissipations are less and the coherence is higher for larger number of molecules. We also found that the power spectrum of autocorrelation functions show resonance peak at the frequency of coherent oscillations. The peak is less prominent for smaller number of molecules and less barrier height and therefore can be used as another measure of stability of oscillations. As a consequence of nonzero probability flux, we show that the three-point correlations from the time traces show irreversibility, providing a possible way to explore the flux from the observations. Furthermore, we explored the escape time from the oscillation ring to outside at different molecular number. We found that when barrier height is higher, escape time is longer and phase coherence of oscillation is higher. Finally, we performed the global sensitivity analysis of the underlying parameters to find the key network wirings responsible for the stability of the oscillation system.
Co-reporter:Zuojia Liu, Xiliang Zheng, Xiurong Yang, Erkang Wang, Jin Wang
Biophysical Journal (20 May 2009) Volume 96(Issue 10) pp:
Publication Date(Web):20 May 2009
DOI:10.1016/j.bpj.2008.12.3965
The affinity and specificity of drugs with human serum albumin (HSA) are crucial factors influencing the bioactivity of drugs. To gain insight into the carrier function of HSA, the binding of levamlodipine with HSA has been investigated as a model system by a combined experimental and theoretical/computational approach. The fluorescence properties of HSA and the binding parameters of levamlodipine indicate that the binding is characterized by one binding site with static quenching mechanism, which is related to the energy transfer. As indicated by the thermodynamic analysis, hydrophobic interaction is the predominant force in levamlodipine-HSA complex, which is in agreement with the computational results. And the hydrogen bonds can be confirmed by computational approach between levamlodipine and HSA. Compared to predicted binding energies and binding energy spectra at seven sites on HSA, levamlodipine binding HSA at site I has a high affinity regime and the highest specificity characterized by the largest intrinsic specificity ratio (ISR). The binding characteristics at site I guarantee that drugs can be carried and released from HSA to carry out their specific bioactivity. Our concept and quantification of specificity is general and can be applied to other drug-target binding as well as molecular recognition of peptide-protein, protein-protein, and protein-DNA interactions.
Co-reporter:Jin Wang, Li Xu, Erkang Wang
Biophysical Journal (2 December 2009) Volume 97(Issue 11) pp:
Publication Date(Web):2 December 2009
DOI:10.1016/j.bpj.2009.09.021
Three-protein circadian oscillations in cyanobacteria sustain for weeks. To understand how cellular oscillations function robustly in stochastic fluctuating environments, we used a stochastic model to uncover two natures of circadian oscillation: the potential landscape related to steady-state probability distribution of protein concentrations; and the corresponding flux related to speed of concentration changes which drive the oscillations. The barrier height of escaping from the oscillation attractor on the landscape provides a quantitative measure of the robustness and coherence for oscillations against intrinsic and external fluctuations. The difference between the locations of the zero total driving force and the extremal of the potential provides a possible experimental probe and quantification of the force from curl flux. These results, correlated with experiments, can help in the design of robust oscillatory networks.
Co-reporter:Jin Wang, Bo Huang, Xuefeng Xia, Zhirong Sun
Biophysical Journal (18 July 2012) Volume 103(Issue 2) pp:374
Publication Date(Web):18 July 2012
DOI:10.1016/j.bpj.2012.06.033
Co-reporter:Jin Wang, Li Xu, Erkwang Wang
Biophysical Journal (15 June 2007) Volume 92(Issue 12) pp:
Publication Date(Web):15 June 2007
DOI:10.1529/biophysj.107.105551
Biomolecular associations often accompanied by large conformational changes, sometimes folding and unfolding. By exploring an exactly solvable model, we constructed the free energy landscape and established a general framework for studying the biomolecular flexible binding process. We derived an optimal criterion for the specificity and function for flexible biomolecular binding where the binding and conformational folding are coupled.
Co-reporter:Dan Li, Zuojia Liu, Wenjing Zhao, Xiliang Zheng, Jin Wang, Erkang Wang
European Journal of Pharmaceutical Sciences (12 March 2013) Volume 48(Issues 4–5) pp:658-667
Publication Date(Web):12 March 2013
DOI:10.1016/j.ejps.2012.12.023
Pancreatic cancer is one of the most malignant tumor diseases with the characters of aggressive growth and metastasis. With the inefficiency of the current therapeutics, new potential targets and new therapeutic agents for healing of pancreatic cancer are critically needed. We have previously found a small molecule, named 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP, NSC number: 48160), which can freeze the intermediate of Ras-GTP hydrolysis in the open non-signaling conformation with high affinity and high specificity in silico. In this work, we studied the effect and mechanism of TBMMP on two pancreatic cancer cell lines, CFPAC-1 and BxPC-3. The results showed that TBMMP could restrain the growth of the pancreatic cancer cells with IC50 value 84.3 μM for CPFAC-1 and 94.5 μM for BxPC-3, respectively. Additionally, TBMMP increased cytochrome c release, reduced mitochondrial membrane potential, activated caspase-3, -9, elevated ROS and increased expression of the Bax in the pancreatic cancer cell lines. The results indicated that TBMMP induced the apoptosis of pancreatic cancer cells through the mitochondrial pathway. Further, we also found that TBMMP could suppress the metastasis of both pancreatic cancer cells in vitro. Taken together, we proposed that TBMMP might be a therapeutic potential lead for treating patients with pancreatic cancer.Download high-res image (155KB)Download full-size image
Co-reporter:Kun Zhang, Jing Liu, Erkang Wang, Jin Wang
Physica A: Statistical Mechanics and its Applications (1 April 2017) Volume 471() pp:757-766
Publication Date(Web):1 April 2017
DOI:10.1016/j.physa.2016.12.044
•Path integral approach to the statistical distributions of option pricing.•Analytical expressions of statistical distribution of bond and bond option pricing.•Statistical fluctuations and fatty tails of bond and bond option pricing.Derivative (i.e. option) pricing is essential for modern financial instrumentations. Despite of the previous efforts, the exact analytical forms of the derivative pricing distributions are still challenging to obtain. In this study, we established a quantitative framework using path integrals to obtain the exact analytical solutions of the statistical distribution for bond and bond option pricing for the Vasicek model. We discuss the importance of statistical fluctuations away from the expected option pricing characterized by the distribution tail and their associations to value at risk (VaR). The framework established here is general and can be applied to other financial derivatives for quantifying the underlying statistical distributions.
Co-reporter:Jiangtao Ren, Jiahai Wang, Lei Han, Erkang Wang and Jin Wang
Chemical Communications 2011 - vol. 47(Issue 38) pp:NaN10565-10565
Publication Date(Web):2011/08/22
DOI:10.1039/C1CC13973H
Kinetically grafting G-quadruplexes onto one-dimensional DNA nanostructures with precise positioning was realized in this study. The programs hold great promise for label-free and enzyme-free detection of various targets as a result of signal amplification from G-quadruplexes, and building DNA nanostructures as scaffolds due to the molecular recognition capacity of G-quadruplex aptamers.
Co-reporter:Yongliang Yang, Guohui Li, Dongyu Zhao, Haoyang Yu, Xiliang Zheng, Xiangda Peng, Xiaoe Zhang, Ting Fu, Xiaoqing Hu, Mingshan Niu, Xuefei Ji, Libo Zou and Jin Wang
Chemical Science (2010-Present) 2015 - vol. 6(Issue 5) pp:NaN2821-2821
Publication Date(Web):2015/01/13
DOI:10.1039/C4SC03416C
Cognition and memory impairment are hallmarks of the pathological cascade of various neurodegenerative disorders. Herein, we developed a novel computational strategy with two-dimensional virtual screening for not only affinity but also specificity. We integrated the two-dimensional virtual screening with ligand screening for 3D shape, electrostatic similarity and local binding site similarity to find existing drugs that may reduce the signs of cognitive deficits. For the first time, we found that pazopanib, a tyrosine kinase inhibitor marketed for cancer treatment, inhibits acetylcholinesterase (AchE) activities at sub-micromolar concentration. We evaluated and compared the effects of intragastrically-administered pazopanib with donepezil, a marketed AchE inhibitor, in cognitive and behavioral assays including the novel object recognition test, Y maze and Morris water maze test. Surprisingly, we found that pazopanib can restore memory loss and cognitive dysfunction to a similar extent as donepezil in a dosage of 15 mg kg−1, only one fifth of the equivalent clinical dosage for cancer treatment. Furthermore, we demonstrated that pazopanib dramatically enhances the hippocampal Ach levels and increases the expression of the synaptic marker SYP. These findings suggest that pazopanib may become a viable treatment option for memory and cognitive deficits with a good safety profile in humans.
Co-reporter:Zaizhi Lai, Kun Zhang and Jin Wang
Physical Chemistry Chemical Physics 2014 - vol. 16(Issue 14) pp:NaN6495-6495
Publication Date(Web):2014/02/17
DOI:10.1039/C3CP54476A
We explore the multi-dimensional diffusion dynamics of protein conformational change. We found in general that the diffusion is anisotropic and inhomogeneous. The directional and positional dependence of diffusion have significant impacts on the protein conformational kinetics: the dominant kinetic path of conformational change is shifted from the naively expected steepest decent gradient paths. The kinetic transition state is shifted away from the transition state. The effective kinetic free energy barrier height, determining the kinetic rate of the conformational change, is shifted away from the one estimated from the thermodynamic free energy barrier. The shift of the transition state in position and value will modify the phi value analysis for identification of hot residues and interactions responsible for conformational dynamics. Ongoing and future experiments can test the predictions of the model.
Co-reporter:Cong Chen, Kun Zhang, Haidong Feng, Masaki Sasai and Jin Wang
Physical Chemistry Chemical Physics 2015 - vol. 17(Issue 43) pp:NaN29044-29044
Publication Date(Web):2015/09/24
DOI:10.1039/C5CP04780C
Many physical, chemical and biochemical systems (e.g. electronic dynamics and gene regulatory networks) are governed by continuous stochastic processes (e.g. electron dynamics on a particular electronic energy surface and protein (gene product) synthesis) coupled with discrete processes (e.g. hopping among different electronic energy surfaces and on and off switching of genes). One can also think of the underlying dynamics as the continuous motion on a particular landscape and discrete hoppings among different landscapes. The main difference of such systems from the intra-landscape dynamics alone is the emergence of the timescale involved in transitions among different landscapes in addition to the timescale involved in a particular landscape. The adiabatic limit when inter-landscape hoppings are fast compared to continuous intra-landscape dynamics has been studied both analytically and numerically, but the analytical treatment of the non-adiabatic regime where the inter-landscape hoppings are slow or comparable to continuous intra-landscape dynamics remains challenging. In this study, we show that there exists mathematical mapping of the dynamics on 2N discretely coupled N continuous dimensional landscapes onto one single landscape in 2N dimensional extended continuous space. On this 2N dimensional landscape, eddy current emerges as a sign of non-equilibrium non-adiabatic dynamics and plays an important role in system evolution. Many interesting physical effects such as the enhancement of fluctuations, irreversibility, dissipation and optimal kinetics emerge due to non-adiabaticity manifested by the eddy current illustrated for an N = 1 self-activator. We further generalize our theory to the N-gene network with multiple binding sites and multiple synthesis rates for discretely coupled non-equilibrium stochastic physical and biological systems.
Co-reporter:Zhedong Zhang and Jin Wang
Physical Chemistry Chemical Physics 2015 - vol. 17(Issue 37) pp:NaN23760-23760
Publication Date(Web):2015/08/14
DOI:10.1039/C5CP03623B
We analytically investigate the population and coherence dynamics and relaxations in the vibrational energy transport in molecules. The corresponding two time scales t1 and t2 are explored. Coherence-population entanglement is found to considerably promote the time scale t2 for dephasing and the amplitude of coherence. This is attributed to the suppression of the environment-induced drift force by coherence. Moreover the population imbalance (magnetization) is shown to be significantly amplified with the coherence-population entanglement. Contrary to the previous studies, we exactly elucidate a coherent process by showing t1 < t2. We predict the relaxation of vibrational and orientational dynamics of OH-stretching modes in agreement with the recent experiments, when applied to the water molecules dissolved in D2O. Finally we explore the coherence effect on the heat current at the macroscopic level.
Co-reporter:Xiliang Zheng and Jin Wang
Physical Chemistry Chemical Physics 2016 - vol. 18(Issue 12) pp:NaN8578-8578
Publication Date(Web):2016/02/25
DOI:10.1039/C5CP06416C
We investigated the main universal statistical distributions of single molecular recognition. The distributions of the single molecule binding free energy spectrum or density of states were characterized in the ligand–receptor binding energy landscape. The analytical results are consistent with the microscopic molecular simulations. The free energy distribution of different binding modes or states for a single molecule ligand receptor pair is approximately Gaussian near the mean and exponential at the tail. The equilibrium constant of single molecule binding is log-normal distributed near the mean and power law distributed near the tail. Additionally, we found that the kinetics distribution of single molecule ligand binding can be characterized by log-normal around the mean and power law distribution near the tail. This distribution is caused by exploration of the underlying inhomogeneous free energy landscape. Different ligand–receptor binding complexes have the same universal form of distribution but differ in parameters.
Co-reporter:Haidong Feng, Kun Zhang and Jin Wang
Chemical Science (2010-Present) 2014 - vol. 5(Issue 10) pp:NaN3769-3769
Publication Date(Web):2014/06/26
DOI:10.1039/C4SC00831F
Transition state or Kramers' rate theory has been used to quantify the kinetic speed of many chemical, physical and biological equilibrium processes successfully. For non-equilibrium systems, the analytical quantification of the kinetic rate is still challenging. We developed a new transition state or Kramers' rate theory for general non-equilibrium stochastic systems with finite fluctuations. We illustrated that the non-equilibrium rate is mainly determined by the exponential factor as the weight action measured from the basin of attraction to the “saddle” or more accurately “global maximum” point on the optimal path rather than the saddle point of the underlying landscape as in the conventional transition state or Kramers' rate formula for equilibrium systems. Furthermore, the pre-factor of the non-equilibrium rate is determined by the fluctuations around the basin of attraction and “saddle” point along the optimal paths. We apply our theory for non-equilibrium rate to fate decisions in stem cell differentiation. The dominant kinetic paths between stem and differentiated cell basins are irreversible and do not follow the gradient path along the landscape. This reflects that the dynamics of non-equilibrium systems is not only determined by the landscape gradient but also the curl flux, suggesting experiments to test theoretical predictions. We calculated the transition rate between cell fates. The predictions are in good agreements with stochastic simulations. Our general rate and path formula can be applied to other non-equilibrium systems.
Co-reporter:Zhiqiang Yan, Xiliang Zheng, Erkang Wang and Jin Wang
Chemical Science (2010-Present) 2013 - vol. 4(Issue 6) pp:NaN2395-2395
Publication Date(Web):2013/04/04
DOI:10.1039/C3SC50478F
Binding affinity and specificity are crucial for biomolecular recognition. Past studies have focused on binding affinity while the quantification of specificity has remained an elusive challenge. The conventional specificity measures the discrimination of the specific receptor against others for a ligand binding. It is difficult to explore all the possible competing receptors for the ligand. Here, we quantified the thermodynamic intrinsic specificity of discriminating the “native” binding mode against the “non-native” binding modes. Intrinsic specificity is relatively easy to compute since one doesn't need to explore all the other receptors. We found that the thermodynamic intrinsic specificity correlates with the conventional specificity. This validates the statistical equivalence of conventional and intrinsic specificities for receptors at reasonable size. We also computationally quantified the residence time of a ligand on the receptor target as the kinetic specificity. We found that the kinetic specificity correlates with the thermodynamic intrinsic specificity and the binding affinity, suggesting the kinetics and the thermodynamics can be simultaneously optimized for biological activities. With the thermodynamic and kinetic specificities in addition to affinity, we carried out a drug screening test on the target cyclooxygenase-2 (COX-2). We showed that multidimensional (two- and three-dimensional) screening has higher capability than affinity alone to discriminate the drug target (COX-2) from the competitive receptor (COX-1), and the selective drugs from the non-selective drugs. Our work suggests a new way of multidimensional drug screening and target identification, which has significant potential applications for drug discovery and design.
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