Vitamin E (α-tocopherol; TPGS) micelle is a robust nanocarrier in delivering hydrophobic active pharmaceutical ingredients, but it is suffering from poor stability that is essential in terms of pharmaceutical and biomedical applications. Taking advantage of the chirality of vitamin E, this work reports the stereoselective stabilization of polymer-vitamin E conjugate micelles. Vitamin E was covalently linked to multivalent methoxy poly(ethylene glycol)-co-poly(glutamic acid), generating amphiphilic conjugates that could self-assemble into micelles. Eight types of micelles were produced via tailored combination of polymer backbone and side chain with different chirality. The particle size and critical micelle concentration analysis demonstrated a correlation between conjugate chirality and micelle stability. The most stable micelles were obtained when poly(glutamic acid) and vitamin E both are dextrorotatory, because of the high degree of α-helix revealed by both circular dichroism spectroscopy and molecular dynamics simulation. This phenomenon was further verified by the fluorescence resonance energy transfer (FRET) analysis in HepG2 cells. The current work not only provides a method to enhance the stability of vitamin E micelles, but also adds an additional facile tool in regulating the stability of polymer conjugate micelles without changing the conjugate composition.

Classical molecular dynamic (MD) simulation of membrane proteins faces significant challenges in accurately reproducing and predicting experimental observables such as ion conductance and permeability due to its incapability of precisely describing the electronic interactions in heterogeneous systems. In this work, the free energy profiles of K+ and Na+ permeating through the gramicidin A channel are characterized by using the AMOEBA polarizable force field with a total sampling time of 1 μs. Our results indicated that by explicitly introducing the multipole terms and polarization into the electrostatic potentials, the permeation free energy barrier of K+ through the gA channel is considerably reduced compared to the overestimated results obtained from the fixed-charge model. Moreover, the estimated maximum conductance, without any corrections, for both K+ and Na+ passing through the gA channel are much closer to the experimental results than any classical MD simulations, demonstrating the power of AMOEBA in investigating the membrane proteins.

Fluorescent RNA aptamer Spinach can bind and activate a green fluorescent protein (GFP)-like chromophore (an anionic DFHBDI chromophore) displaying green fluorescence. Spectroscopic properties, spectral tuning, and the photoisomerization mechanism in the Spinach-DFHBDI complex have been investigated by high-level QM and hybrid ONIOM(QM:AMBER) methods (QM method: (TD)DFT, SF-BHHLYP, SAC-CI, LT-DF-LCC2, CASSCF, or MS-CASPT2), as well as classical molecular dynamics (MD) simulations. First, our benchmark calculations have shown that TD-DFT and spin-flip (SF) TD-DFT (SF-BHHLYP) failed to give a satisfactory description of absorption and emission of the anionic DFHBDI chromophore. Comparatively, SAC-CI, LT-DF-LCC2, and MS-CASPT2 can give more reliable transition energies and are mainly used to further study the spectra of the anionic DFHBDI chromophore in Spinach. The RNA environmental effects on the spectral tuning and the photoisomerization mechanism have been elucidated. Our simulations show that interactions of the anionic cis-DFHBDI chromophore with two G-quadruplexes as well as a UAU base triple suppress photoisomerization of DFHBDI. In addition, strong hydrogen bonds between the anionic cis-DFHBDI chromophore and nearby nucleotides facilitate its binding to Spinach and further inhibit the cis-trans photoisomerization of DFHBDI. Solvent molecules, ions, and loss of key hydrogen bonds with nearby nucleotides could induce dissociation of the anionic trans-DFHBDI chromophore from the binding site. These results provide new insights into fluorescent RNA Spinach and may help rational design of other fluorescent RNAs.

In this work, we attempt to apply a coarse-grained (CG) model, which is based on anisotropic Gay–Berne and electric multipole (EMP) potentials, to the modeling of nucleic acids. First, a comparison has been made between the CG and atomistic models (AMBER point-charge model) in the modeling of DNA and RNA hairpin structures. The CG results have demonstrated a good quality in maintaining the nucleic acid hairpin structures, in reproducing the dynamics of backbone atoms of nucleic acids, and in describing the hydrogen-bonding interactions between nucleic acid base pairs. Second, the CG and atomistic AMBER models yield comparable results in modeling double-stranded DNA and RNA molecules. It is encouraging that our CG model is capable of reproducing many elastic features of nucleic acid base pairs in terms of the distributions of the interbase pair step parameters (such as shift, slide, tilt, and twist) and the intrabase pair parameters (such as buckle, propeller, shear, and stretch). Finally, The GBEMP model has shown a promising ability to predict the melting temperatures of DNA duplexes with different lengths.

Modeling structural and thermodynamic properties of nucleic acids has long been a challenge in the development of force fields. Polarizable force fields are a new generation of potential functions to take charge redistribution and induced dipole into account, and have been proved to be reliable to model small molecules, polypeptides and proteins, but their use on nucleic acids is still rather limited. In this article, the interactions between nucleic acids and a small molecule or ion were modeled by AMOEBAbio09, a modern polarizable force field, and conventional non-polarizable AMBER99sb and CHARMM36 force fields. The resulting intermolecular interaction energies were compared with those calculated by ab initio quantum mechanics methods. Although the test is not sufficient to prove the reliability of the polarizable force field, the results at least validate its capability in modeling energetics of static configurations, which is one basic component in force field parameterization.

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.

An unprecedented N-heterocyclic carbene catalytic reductive β,β-carbon coupling of α,β-nitroalkenes, by using an organic substrate to mimic the one-electron oxidation role of the pyruvate ferredoxin oxidoreductase (PFOR) in living systems, has been developed. The reaction goes through a radical anion intermediate generated under a catalytic redox process. For the first time, the presence of radical anion intermediate in NHC organocatalysis is observed and clearly verified.

RNA-dependent RNA polymerases (RdRps) are enzymes catalyzing RNA replication from a RNA template. Active-site closure in RdRps, normally induced by correct nucleotide triphosphate (NTP) binding, is a prerequisite for the cycle of nucleotide incorporation. So, a complete understanding of polymerase function (in particular polymerase fidelity) of a RdRp requires more complete knowledge of active-site closure in the RdRp. In this work, based on solved crystal structures, we have built different models for the RNA-dependent RNA polymerase from poliovirus (termed PV 3Dpol). Through MD simulations and free energy calculations of these PV 3Dpol models, we have revealed the dynamic correlation between motif A and motif D and between motif A and incoming NTP, have deepened our understanding of polymerase fidelity from dynamic aspects, and have provided an explanation to the puzzle that arises from different observations based on kinetic studies and structural data.

Gay–Berne anisotropic potential has been widely used to evaluate the nonbonded interactions between coarse-grained particles being described as elliptical rigid bodies. In this paper, we are presenting a coarse-grained model for twenty kinds of amino acids and proteins, based on the anisotropic Gay–Berne and point electric multipole (EMP) potentials. We demonstrate that the anisotropic coarse-grained model, namely GBEMP model, is able to reproduce many key features observed from experimental protein structures (Dunbrack Library), as well as from atomistic force field simulations (using AMOEBA, AMBER, and CHARMM force fields), while saving the computational cost by a factor of about 10–200 depending on specific cases and atomistic models. More importantly, unlike other coarse-grained approaches, our framework is based on the fundamental intermolecular forces with explicit treatment of electrostatic and repulsion-dispersion forces. As a result, the coarse-grained protein model presented an accurate description of nonbonded interactions (particularly electrostatic component) between hetero/homodimers (such as peptide–peptide, peptide–water). In addition, the encouraging performance of the model was reflected by the excellent correlation between GBEMP and AMOEBA models in the calculations of the dipole moment of peptides. In brief, the GBEMP model given here is general and transferable, suitable for simulating complex biomolecular systems.

•The first transcriptome for Tetraselmis subcordiformis' special hydrogen inducing behavior.•Overall changing pattern of transcription for microalgal H2 evaluation process.•Quantitative analysis unveiled the functions of different hydrogenase subunits.•Postulated mechanism for anaerobic dark induction of T. subcordiformis.•Global gene function analysis showed T. subcordiformis a good candidate for biofuel.It's the first comparative transcriptome study of Tetraselmis subcordiformis' H2 production with carbonyl cyanide m-chlorophenylhydrazone (CCCP) by de novo RNA-seq. The global analysis of the annotated genes and pathways unveiled it a good candidate for biofuels. Focusing on H2 production, the genes coding active center subunit (HydA) and assembly subunits (HydEF and HydG) of hydrogenase proportionally expressed during the induction but stopped after illuminated; on contrast, the gene of the active centre stabilization subunit (Hyd3) highly expressed during the H2 evolution, indicating its key role in the prolonged H2 production. The results also showed genes of HCP4, ppGpp phosphohydrolase and RpoD relating to the hydrogenase expression regulation. On the energy aspect, genes of CF-ATPases and ferredoxin-NADP reductase in chloroplast down-regulated while Mito-ATPase in mitochondria and pyruvate metabolism pathway up-regulated during the H2 production, consisting with our previous reports on physiological level.

A substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones is disclosed. Acid co-catalysts play vital roles in control of the reaction pathways, allowing for individual access to diverse products from identical substrates.

In this work, we have investigated in details the origin of the assembly of the DAP12 dimer with only one NKG2C in the activating immunoreceptor complex from thew two aspects of electronic properties and dynamic structures by performing density functional theory (DFT) calculations and molecular dynamics (MD) simulations. In the DFT calculations, we studied the aggregation ability of the NKG2CTM with the DAP12TM dimer and the DAP12TM–DAP12TM–NKG2CTM complex by analyzing the electrostatic potentials and frontier molecular orbitals (FMOs), and in the MD simulations we mainly investigated the dynamic structures of the DAP12TM–DAP12TM–NKG2CTM complex and its mutants, as well as the tetramer complex consisting of two DAP12TM and two NKG2CTM helixes without any restriction. Through the studies of the electrostatic potential, the FMOs, and the dynamic structures, we have provided reasonable explanations to some extent for the experimental observation that only one NKG2C can associate with the DAP12 homodimer. The present theoretical results are expected to give valuable information for further studying the assembly between receptors and signaling subunits.

BM2 channel plays an important role in the replication of influenza virus B. However, few studies attempt to investigate the mechanism of the proton conductance in BM2 channel, as well as the drug resistance of the BM2 channel. The first experimental structure of the BM2 protein channel has recently been solved, enabling us to theoretically study BM2 systems with different protonation states of histidine. By performing molecular dynamics simulations on the BM2 systems with different protonation states of four His19 residues, we provided our understanding of the structure, dynamics, and drug resistance of the BM2 channel. In general, the results of our study and other investigations both have demonstrated that whether the BM2 channel adopts an open or a closed form depends on the protonation state of His19. Meanwhile, we discovered that a drug (amantadine) was unable to enter into the center of the BM2 channel even at a low pH condition probably due to the number of hydrophilic residues of the BM2 channel. Finally, potentials of mean force (PMF) calculations were performed for the drug binding BM2 channel, energetically explaining why the BM2 channel exhibited drug resistance to two inhibitors of the AM2 channel, amantadine and rimantadine.

Molecular dynamics (MD) simulations followed by principal component analysis were performed to study the conformational change of MDM2 induced by p53 and two inhibitor (P4 and MI63a) bindings. The results show that the hydrophobic cleft of MDM2 is very flexible and adaptive to different structural binding partners. The cleft tends to become wider and more stable as MDM2 binds to the three binding partners, while unbound MDM2 shows a narrower and pretty flexible cleft, which agrees with recent experimental data and theoretical studies. It was also found that the binding of P4 and p53 stabilizes the motion of the loop L2 linking the helix α2 and β strand (β3), but the presence of MI63a makes the motion of L2 disordered. In addition, the binding free energies of the three partners to MDM2 were calculated using molecular mechanics generalized Born surface area to explain the binding modes of these three partners to MDM2. This study will be helpful not only for better understanding the functional, concerted motion of MDM2, but also for the rational design of potent anticancer drugs targeting the p53–MDM2 interaction.

Coarse-grained studies of CH3SH, CH3CHO and CHCl3 liquids, based on anisotropic Gay-Berne (GB) and electric multipole potentials (EMP), demonstrate that the coarse-grained model is able to qualitatively reproduce the results obtained from the atomistic model (AMOEBA polarizable force field) and allows for significant saving in computation time. It should be pointed out that the accuracy of the coarse-grained model is very sensitive to how well the anisotropic GB particle is defined and how satisfactorily the EMP sites are chosen.

Inhibition of the MDM2–p53 interaction is considered to be a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses were used to study the inhibitory mechanisms of four small molecule inhibitors, K23, YIN, DIZ and IMZ on the p53–MDM2 interaction. We found excellent agreement between the rank of the calculated absolute binding free energies using the MM-GBSA method and the experimentally determined rank. The results show that van der Waals energy is the dominant factor for the binding of the four inhibitors. Statistical analyses of the hydrophobic contacts between the inhibitors and MDM2 were performed, and the results suggested that these inhibitors form stable hydrophobic interactions with six residues of MDM2: Leu54, Gly58, Ile61, Met62, Val93 and His96. Calculations of the detailed van der Waals interactions between non-peptide inhibitors and individual protein residues can provide insights into the inhibitor-protein binding mechanism. Our studies suggest that the CH–π and π–π interactions between the four inhibitors and protein residues drive binding of the inhibitors in the hydrophobic cleft of MDM2.Graphical abstractGeometries of key residues, which produce some favorable interactions with the inhibitor IMZ is plotted in the complexes according to the lowest-energy structure from the MD trajectory.Download high-res image (135KB)Download full-size imageHighlights► Statistical analyses of hydrophobic contacts suggest that the selected four inhibitors form stable hydrophobic interactions with six residues Leu54, Gly58, Ile61, Met62, Val93 and His96. ► Residue-based binding free energy decomposition analysis shows that the CH–π and π–π interactions between four inhibitors and residues drive the bindings of the inhibitors in hydrophobic cleft of MDM2. ► The calculation of binding free energy indicates that van der Waals interactions drive the bindings of the inhibitors K23, YIN, DIZ and IMZ to MDM2.

Seven pairs of epimers and one pair of isomeric metabolites of taxanes, each pair of which have similar structures but different retention behaviors, together with additional 13 taxanes with different substitutions were chosen to investigate the quantitative structure-retention relationship (QSRR) of taxanes in ultra fast liquid chromatography (UFLC). Monte Carlo variable selection (MCVS) method was adopted to choose descriptors. The selected four descriptors were used to build QSRR model with multi-linear regression (MLR) and artificial neural network (ANN) modeling techniques. Both linear and nonlinear models show good predictive ability, of which ANN model was better with the determination coefficient R2 for training, validation and test set being 0.9892, 0.9747 and 0.9840, respectively. The results of 100 times’ leave-12-out cross validation showed the robustness of this model. All the isomers can be correctly differentiated by this model. According to the selected descriptors, the three dimensional structural information was critical for recognition of epimers. Hydrophobic interaction was the uppermost factor for retention in UFLC. Molecules’ polarizability and polarity properties were also closely correlated with retention behaviors. This QSRR model will be useful for separation and identification of taxanes including epimers and metabolites from botanical or biological samples.

A substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones is disclosed. Acid co-catalysts play vital roles in control of the reaction pathways, allowing for individual access to diverse products from identical substrates.

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.