To improve sampling of the configurational entropy change upon protein–ligand binding, we have introduced a new set of coarse variables describing the relative orientation and position of the ligand via a global macromolecular orientational procedure, onto which geometrical restraints are applied. Evaluating the potential of mean force for the different coarse variables, the experimental standard binding free energy for three decapeptides associated with the SH3 domain of the Abl kinase is reproduced quantitatively.

We have investigated at the atomic level amide-based rotaxanes set in motion in four different solvents, namely, ethyl ether, acetonitrile, ethanol and water. In three non-aqueous solvents, shuttling of the macrocycle between two binding sites separated by a free-energy barrier is coupled with a conformational change and rotation, driven primarily by hydrogen-bonding interactions. The mechanism that underlies the shuttling is completely altered when the non-aqueous solvent is replaced by water. In aqueous solution, hydrophobic interactions chiefly control shuttling of the rotaxane, leading to a sharp decrease of the free-energy barrier, thereby speeding up the process. The binding sites and the reaction pathway describing shuttling vary significantly in water compared with in the other three solvents. We found that the high polarity, the hydrogen-bond donor and acceptor ability, and the minimal steric hindrance of water conspire to modify the mechanism. These three physicochemical properties are also responsible for the lubrication by water. That water completely changes the mechanism underlying the shuttling of rotaxanes, is addressed for the first time in this study, and provides valuable guidelines for the de novo design of molecular machines.

Disentangling the different movements observed in rotaxanes is critical to characterize their function as molecular and biological motors. How to achieve unidirectional rotation is an important question for successful construction of a highly efficient molecular motor. The motions within a rotaxane composed of a benzylic amide ring threaded on a fumaramide moiety were investigated employing atomistic molecular dynamics simulations. The free-energy profiles describing the rotational process of the ring about the thread were determined from multi-microsecond simulations. Comparing the theoretical free-energy barriers with their experimental counterpart, the syn–anti isomerization of the amide bond within the ring was ruled out. The free-energy barriers arise in fact from the disruption of hydrogen bonds between the ring and the thread. Transition path analysis reveals that complete description of the reaction coordinate requires another collective variable. The free-energy landscape spanned by the two variables characterizing the coupled rotational and shuttling processes of the ring in the rotaxane was mapped. The calculated free-energy barrier, amounting to 9.3 kcal mol−1, agrees well with experiment. Further analysis shows that shuttling is coupled with the isomerization of the ring, which is not limited to a simplistic chair-to-chair transition. This work provides a cogent example that contrary to chemical intuition, molecular motion can result from complex, entangled movements requiring for their accurate description careful modeling of the underlying reaction coordinate. The methodology described here can be used to evaluate the different components of the multifaceted motion in rotaxanes, and constitutes a robust tool for the rational design of molecular machines.

Pillararene-based [2]rotaxanes have gained notoriety since the synthesis of the first pillar[5]arene in 2008. The marked propensity of pillararenes to bind cationic groups is often utilized to prepare functional host–guest complexes. Interestingly enough, the interaction of pillararenes with cationic groups is modulated by the nature of the solvent. The molecular mechanism that underlies binding, examined experimentally, remains, however, partially understood. In the present contribution, the solvent-controlled motion in a [2]rotaxane composed of a 1,4-diethoxypillar[5]arene (P[5]) ring threaded onto an hydrogen-bond donor imidazolium axle was investigated in eight different solvents. Apart from the polarity, the hydrogen-bond-accepting ability of the solvent was considered with particular care. In environments featuring hydrogen-bond acceptors, the P[5] tends to include the alkyl chain at one end of the axle, staying away from the cationic imidazolium unit at the other end of it. Inclusion is primarily driven by the favorable interaction of the alkyl chain with the P[5], alongside the hydrogen-bonding interaction of the imidazolium moiety with the solvent. However, in a low-polarity solvent, devoid of hydrogen-bond acceptors, the P[5] binds favorably the imidazolium moiety and the neighboring methylene groups, resulting in hydrogen bonds established between the imidazolium moiety and the P[5], and the unusual C–H···π interaction of the methylene groups adjacent to the imidazolium moiety with the benzene rings of the P[5]. The present results have important bearings on the design of artificial molecular machines formed by pillararenes and cationic moieties.

In cyclodextrin (CD)-based rotaxanes, the shuttling rate of the macrocycle along the thread is crucial to characterize their function as molecular machines. In general, the composition of the thread and the environment are considered to be important factors affecting the nature of the movement. Yet, the role of ancillary motions on the shuttling rate remains unclear. In the present contribution, two rotaxanes having the same components, yet significantly different shuttling rates between two stable states in an aqueous environment, have been investigated at the atomic level using numerical simulations. These two rotaxanes consist of an axle with two stations linked by a 2-methylpyridinium group and an α-CD sliding on the axle and assuming two different orientations. We found that a number of cyclodextrin glucopyranose units (GLUs) isomerized during shuttling, which we anticipate to affect the shuttling rate. The two-dimensional free-energy landscapes characterizing the isomerization of the GLUs and the shuttling along the thread were mapped and revealed that the energetic barriers hampering spontaneous transition between the two stations significantly differ for the two rotaxanes. Structural analysis shows that this difference mainly arises from steric hindrances caused by the methyl substituent of the pyridinium group, which leads to a different number of the GLUs experiencing conformational change during shuttling. Moreover, the thermodynamic stability of the complex is found to be distinct between the two rotaxanes. This discrepancy may be ascribed to the dipole moment of the complex, which is sensitive to the orientation of CD. It can be concluded that shuttling in the rotaxanes is not only highly coupled with isomerization of GLUs but also affected by thermodynamic stability, resulting in a shuttling rate sensitive to the orientation of the CD. The present results help understand the complex molecular motion in CD-based molecular shuttles, and are expected to serve in the design of molecular filters for selectively screening molecules with a specific orientation.

In supramolecular wrapping chemistry, polysaccharides are widely used as wrapping agents for the dissolution, dispersion and functionalization of carbon nanotubes. It is, therefore, of paramount importance to understand the effect of the topology – specifically the linkage – of the polymer chain on its spatial arrangement around the hollow tubular structure, and, hence, on the configuration and the nature of the supramolecular complex. To this end, the β-1,4, α-1,4 and β-1,3-glucans were chosen to wrap a single-walled carbon nanotube (SWCNT) as three prototypical assemblies. Molecular simulations reveal that α-1,4-glucan has the ability to wrap SWCNTs very tightly, whereas β-1,3-glucans can only form irregular helices. The calculated binding affinity of the polysaccharide to the tubular surface follows the order α-1,4 > β-1,4 > β-1,3-glucan. The differences between the three hybrids can be generally described in terms of the inherent propensity of glucans to fold into helices, the hydrophobic interaction of the polysaccharide with the SWCNT, and the formation of intramolecular hydrogen bonds within the polymer chain. The wrapping mode of the glucan chain is mainly determined by its inherent helicity. The hydrophobic interaction is the driving force for helical wrapping. Moreover, the intramolecular hydrogen-bonding interaction can stabilize ideal, compact helical scaffolds. These factors determine the conformation and the binding affinity of the polysaccharide to the SWCNT. The present results can be generalized to other polymers like DNA, and shed new light on the universal principles that underlie the formation of supramolecular complexes using wrapping agents.

In water, a remarkable motion can be observed with a [2]rotaxane, wherein the rotor translocates by reeling its axle in the cavity of an altro-α-CD stopper. Similarly, in aqueous solution, an alkyl altro-α-CD dimer reels its alkyl chain in the altro-α-CD cavity to form a pseudo[1]rotaxane dimer. This reeling motion is in fact induced by the tumbling of the altropyranose unit of an altro-α-CD, a process shown to be solvent-dependent. Tumbling, however, does not occur in low-polarity solvents such as methanol and DMSO. In the present contribution, the mechanism that underlies solvent-controlled tumbling has been studied at the atomic level by means of molecular dynamics simulations combined with microsecond-timescale free-energy calculations. The free-energy profile delineating the tumbling in water of the altropyranose unit of an alkyl altro-α-CD indicates that a 19.8 kcal mol−1 barrier must be overcome to yield the self-inclusion complex, which is the most stable state available to the supramolecular assembly. In DMSO, the free-energy barrier is about 21.0 kcal mol−1 higher, and the self-included alkyl altro-α-CD corresponds to a metastable state. These results provide new thermodynamic and kinetic insights into solvent-controlled tumbling, and reveal the essence of different experimental observations. Further investigation shows that aside from the polarity of the solvent, tumbling of the altro-α-CD derivative stems from the hydrophobicity of the side chain and the propensity of the former to include the latter, which opens perspectives for the design of new, related supramolecular assemblies.

•A method for transferring the spectra measured on multi-instrument is proposed.•Trilinear decomposition is used to calculate the difference between instruments.•Difference between instruments can be corrected by changing a parameter.•Standardization of the spectra measured on multi-instrument was achieved.Calibration model transfer is essential for practical applications of near infrared (NIR) spectroscopy because the measurements of the spectra may be performed on different instruments and the difference between the instruments must be corrected. An approach for calibration transfer based on alternating trilinear decomposition (ATLD) algorithm is proposed in this work. From the three-way spectral matrix measured on different instruments, the relative intensity of concentration, spectrum and instrument is obtained using trilinear decomposition. Because the relative intensity of instrument is a reflection of the spectral difference between instruments, the spectra measured on different instruments can be standardized by a correction of the coefficients in the relative intensity. Two NIR datasets of corn and tobacco leaf samples measured with three instruments are used to test the performance of the method. The results show that, for both the datasets, the spectra measured on one instrument can be correctly predicted using the partial least squares (PLS) models built with the spectra measured on the other instruments.

Binding of cucurbit[6]uril (CB[6]) with the hexamethylene diammonium cation (HD2+) in the presence of sodium ions is elucidated at the atomic level. The most probable complex of CB[6] in saline solution is found to be CB[6]:Na+. A two-stage binding process of CB[6]:Na+ with HD2+ is proposed.

Immobilization of enzymes has attracted much attention in nanoscience and nanotechnology. However, the mechanisms of recognition and immobilization are still poorly understood at atomic resolution. In this study, we report that a newly synthetized single-crystal-like, nanoporous silica particle possesses a high adsorption capacity for the immobilization of papain. The immobilized enzyme could be used in the degradation of proteins, such as bull serum albumin. Moreover, the adsorption mechanism of papain on the silica surface was investigated by employing docking, classical atomistic molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area calculations. Ten independent simulations starting from two representative initial orientations of papain toward the solid surface were performed, resulting in four representative adsorption modes. The calculated relative binding free energies of the four different modes show that the one with the binding patch primarily consisting of an α-helix (ASP108–TYR116), β-sheet (GLN73, ALA76, GLN77), and turn (ARG59) is most energetically favored. Further analysis of the most favored immobilization mode demonstrates that, after initial binding to the silica, the papain optimized its conformation to allow more atoms to contact with the surface. Electrostatic and van der Waals interactions drove the adsorption in a cooperative fashion, wherein van der Waals contributions are the primary component of the binding free energy in the most energetically favored adsorption mode. Besides, the global structure of the papain was preserved in the course of adsorption. Slight structural rearrangements at the entrance of the active site were observed, which increase the accessibility of the active site to solvent and presumably to substrates, and thus could facilitate productive binding between substrates and papain.

Manufacturing at the molecular level engines to power nanocars represents a challenge in the development of nanomachines. A molecular engine formed of β-cyclodextrin (β-CD), aryl, and amide moiety has been studied by means of molecular dynamics simulations combined with free-energy calculations. The compression and decompression strokes involving the binding processes of the (Z)- and (E)-isomers of this engine with 1-adamantanol (AD) have been elucidated by determining the underlying potentials of mean force (PMFs). The difference in the binding-free energies, considered as the work generated by and stored within this engine, is calculated to be +1.5 kcal/mol, in remarkable agreement with the experimentally measured quantity. Partitioning the PMFs into physically meaningful free-energy components suggests that the two binding processes are primarily controlled by the favorable inclusion of AD by the β-CD. The work generated by the engine is harnessed to push the alkyl moiety from the hydrophobic cavity of the CD to water, to modify a dihedral angle by a twisting motion about the C–Cα bond, and to increase the tilt angle between the mean plane of the sugar unit, which connects the amide moiety, and the mean plane of the CD. By deciphering the intricate mechanism whereby the present molecular engine operates, our understanding of how similar nanomachines work is expected to be improved significantly, helping in turn the design of novel, more effective ones.

Employing avant-garde cuisine techniques, in particular sodium alginates, liquid food can be shaped into spheres, thereby conferring to the former original and sometimes unexpected forms and textures. To achieve this result, rational understanding of the science that underlies food physical chemistry is of paramount importance. In this contribution, the process of spherification is dissected for the first time at the atomic level by means of classical molecular dynamics simulations. Our results show that a thin membrane consisting of intertwined alginate chains forms in an aqueous solution containing calcium ions, thereby encapsulating in a sphere the aliment in its liquid state. They also show why the polysaccharide chains will not cohere into such a membrane in a solution of sodium ions. Analysis of the trajectories reveals the emergence of so-called egg-box spatial arrangements, which connect the alginate chains by means of repeated chelation of one calcium ion by two carboxylate groups. Free-energy calculations delineating the formation of these egg-box structures further illuminate the remarkable stability of such tridimensional organizations, which ensures at room temperature the spontaneous growth of the polysaccharide membrane. Spherification has been also examined for liquid aliments of different nature, modeled by charged, hydrophilic and hydrophobic compounds. The membrane-encapsulated food is shaped into robust and durable spheres, irrespective of the liquid core material. By reconciling the views of spherification at small and large scales, the present study lays the groundwork for the rational design of innovative cooking techniques relevant to avant-garde cuisine.

An altro-α-cyclodextrin (altro-α-CD) derivative bearing an adamantyl end group can form a pseudo[1]rotaxane through the self-inclusion of its arm into the CD cavity. Yet, how the bulky end group translocates from the secondary side of the altro-α-CD to its primary side to form the pseudo[1]rotaxane remains somewhat unclear. In the present work, the atomic-level mechanism that underlies the formation of the self-inclusion complex was investigated by means of molecular dynamics simulations combined with microsecond time scale free-energy calculations. Two possible transition pathways leading to the formation of the same self-inclusion structure were considered, namely, threading of the adamantyl group through the altro-α-CD cavity, and tumbling of the altropyranose unit of altro-α-CD. The free-energy profiles characterizing the threading and the tumbling pathways were determined, revealing in each case the free-energy barrier. For the former pathway, the free-energy barrier with respect to the unbound state amounts to 53.6 kcal/mol, unphysically high to make the threading route feasible. Conversely, for the latter pathway, a 16.0 kcal/mol free-energy barrier is measured, indicating that the formation of the pseudo[1]rotaxane may result from the tumbling of the altropyranose unit bearing the adamantyl arm.

γ-Cyclodextrin (γ-CD) and hydroxypropyl-γ-CD (HP-γ-CD) improve the bioavailability of amphotericin B (AmB) while reducing its toxicity. In a recent study, AmB was found to possess two sites within its prolonged macrolide ring, binding to γ-CD. In the present contribution, cooperative binding of AmB to a γ-CD dimer, a hydroxypropyl-γ-CD (HP-γ-CD) dimer and a hybrid dimer formed by the latter two cyclic oligosaccharides was examined by molecular dynamics simulations and free-energy calculations in an aqueous solution. The potentials of mean force (PMFs) characterizing the dimerization of the CDs on the macrolide ring of AmB were determined for four different spatial arrangements, namely head-to-head (H–H), head-to-tail (H–T), tail-to-head (T–H), and tail-to-tail (T–T). The PMFs allowed the most stable supramolecular organization to be identified along the transition coordinate for every possible orientation of the participating cyclic oligosaccharides. To estimate the absolute binding free energy of each spatial arrangement, alchemical transformations were carried out using free-energy perturbation. T−H corresponds to the most stable orientation for the γ-CD dimer, whereas for the HP-γ-CD and hybrid dimers, the H–T motif is preferred. Our simulations also indicate that, among the three different dimers, the hybrid γ-CD/HP-γ-CD possesses the highest binding affinity toward AmB, in line with experiment. Hydrogen-bonding interactions and spatial matching of the host:guest complex play an important role in the cooperative binding of AmB to CD dimers. The difference in the propensity of the three CD dimers to bind AmB can rationalize the experimental observation that the hybrid γ-CD/HP-γ-CD dimer is a better carrier to enhance the bioavailability of AmB.

The clinical use of amphotericin B (AmB), a polyene macrolide antifungal drug, is limited due to its poor bioavailability and pronounced cytotoxicity. Cyclodextrin (CD)-based drug carriers have proven to overcome these shortcomings. In the present contribution, the assembly of AmB with β-CD and γ-CD was investigated systematically using molecular dynamics simulations and free-energy calculations, showing that only the polyene macrolide ring could be included in CDs. The potentials of mean force (PMF) that delineate the process of the macrolide ring entering the cavity of a CD following two possible orientations were determined, revealing distinct inclusion modes for the two CDs. AmB was found to possess two sites within its prolonged macrolide ring where it will bind γ-CD, thereby forming stable complexes—one located at one end of the ring, the other close to the polar head of the drug. Conversely, the macrolide ring cannot enter the cavity of β-CD due to the limited available space. When AmB approaches γ-CD from its primary rim, the AmB:γ-CD complex corresponding to the first binding site was estimated to be energetically favored. Comparison of the free-energy landscapes characterizing the two CDs reveals that γ-CD possesses significantly higher binding affinity to AmB than β-CD, which may explain the experimental observation of their distinct ability to enhance the bioavailability of AmB. Moreover, decomposition of the PMFs into physically meaningful free-energy contributions suggests that van der Waals and electrostatic interactions constitute the main driving forces responsible for the formation of the CD inclusion complexes.

Carbon nanotubes (CNTs) wrapped by polysaccharide chains via noncovalent interactions have been shown to be soluble and dispersed in aqueous environments, and have several potential chemical and biomedical applications. The wrapping mechanism, in particular the role played by the end of the CNT, remains, however, unknown. In this work, a hybrid complex formed by an amylose (AMYL) chain and a single-walled carbon nanotube (SWNT) has been examined by means of atomistic molecular dynamics (MD) simulations to assess its propensity toward self-assembly, alongside its structural characteristics in water. To explore edge effects, the middle and end regions of the SWNT have been chosen as two initial wrapping sites, to which two relative orientations have been assigned, i.e. parallel and orthogonal. The present results prove that AMYL can wrap spontaneously around the tubular surface, starting from the end of the SWNT and driven by both favorable van der Waals attraction and hydrophobic interactions, and resulting in a perfectly compact, helical conformation stabilized by an interlaced hydrogen-bond network. Principal component analysis carried out over the MD trajectories reveals that stepwise burial of hydrophobic faces of pyranose rings controlled by hydrophobic interactions is a key step in the formation of the helix. Conversely, if wrapping proceeds from the middle of the SWNT, self-organization into a helical structure is not observed due to strong van der Waals attractions preventing the hydrophobic faces of the AMYL chain generating enough contacts with the tubular surface.

The relative conformation of the mobile cyclic molecules of a polyrotaxane has been analyzed quantitatively by means of both molecular dynamics and Monte Carlo simulations. Here, the polyrotaxane is formed by several α-cyclodextrins (α-CDs) threaded onto a poly(ethylene glycol) (PEG) chain. The dimerization free energies for three possible spatial arrangements of two consecutive α-CDs, viz., head to head (HH), head to tail (HT), and tail to tail (TT), were determined. The computed dimerization free energies were then introduced into the theoretical framework of a lattice model to predict the percentage of HH and TT motifs in all possible arrangements, employing Monte Carlo simulations. Our results show that this percentage fluctuates when the number of CDs is less than eight and rapidly tends toward 73% when the latter is greater than eight. This theoretical estimate, which is dominated by the dimerization free energy, agrees well with experiments. Deconvolution of the free-energy profiles indicates that dimerization is controlled primarily by the formation of hydrogen bonds between two consecutive α-CDs, hence rationalizing why HH is more favorable than the other two spatial arrangements. The proposed method combining free-energy calculations with a lattice chain model is envisioned to be applied to other 1D chemical or biological self-assembly phenomena to help dissect the mechanisms that underlie the formation of the supramolecular assembly and control the relative conformation of its constituent cyclic compounds.

The design of a bioactive surface with appropriate wettability for effective protein immobilization has attracted much attention. Previous experiments showed that the adsorption of hydrophobic protein HFBI onto a polydimethylsiloxane (PDMS) substrate surface can reverse the inherent hydrophobicity of the surface, hence making it suitable for immobilization of a secondary protein. In this study, atomistic molecular dynamics simulations have been conducted to elucidate the adsorption mechanism of HFBI on the PDMS substrate in an aqueous environment. Nine independent simulations starting from three representative initial orientations of HFBI toward the solid surface were performed, resulting in different adsorption modes. The main secondary structures of the protein in each mode are found to be preserved in the entire course of adsorption due to the four disulfide bonds. The relative binding free energies of the different adsorption modes were calculated, showing that the mode, in which the binding residues of HFBI fully come from its hydrophobic patch, is most energetically favored. In this favorable binding mode, the hydrophilic region of HFBI is fully exposed to water, leading to a high hydrophilicity of the modified PDMS surface, consistent with experiments. Furthermore, a set of residues consisting of Leu12, Leu24, Leu26, Ile27, Ala66, and Leu68 were found to play an important role in the adsorption of HFBI on different hydrophobic substrates, irrespective of the structural features of the substrates.

Rotaxanes driven by solvents have been shown to facilitate translocation of drugs into cells. Shuttling is critical to fulfill this function. Despite the importance of this solvent-driven motion, the mechanism that underlies shuttling remains unclear. In the present contribution, a molecular shuttle controlled by solvent, and formed of α-cyclodextrin (α-CD), dodecamethylene, and bipyridinium moieties, has been studied by means of microsecond time scale molecular dynamics simulations combined with free-energy calculations. Shuttling driven by both solvent and temperature has been investigated by determining the potentials of mean force (PMF) that delineate the process of moving the α-CD along the thread in DMSO and water, at 300 and 400 K. In DMSO, the barriers of the PMFs at both temperatures appear to be virtually the same. At low temperature, however, site exchange of the CD is slowed down. In contrast, the barrier in water is shown to be 4.0 kcal/mol higher than in DMSO, thwarting site exchange. Partitioning the PMFs into free-energy components suggests, in contrast with DMSO, that water interacts favorably with the bipyridium moieties, but less so with the alkyl chain, hence yielding a higher free-energy barrier. This observation is supported by the analysis of the structural features of the rotaxanes from the molecular dynamics trajectories.

Zn2+ in the tumor-suppressor protein p53 DNA-binding domain (DBD) is essential for its structural stability and DNA-binding specificity. Mg2+ has also been recently reported to bind to the p53DBD and influence its DNA-binding activity. In this contribution, the binding geometry of Mg2+ in the p53DBD and the mechanism of how Mg2+ affects its DNA-binding activity were investigated using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Various possible coordination geometries of Mg2+ binding to histidines (His), cysteines (Cys), and water molecules were studied at the B3LYP/6-311+g** level of theory. The protonation state of Cys and the environment were taken into account to explore the factors governing the coordination geometry. The free energy of the reaction to form the Mg2+ complexes was estimated, suggesting that the favorable binding mode changes from a four- to six-coordinated geometry as the number of the protonated Cys increases. Furthermore, MD simulations were employed to explore the binding modes of Mg2+ in the active site of the p53DBD. The simulation results of the Mg2+ system and the native Zn2+ system show that the binding affinity of Mg2+to the p53DBD is weaker than that of Zn2+, in agreement with the DFT calculation results and experiments. In addition, the two metal ions are found to make a significant contribution to maintain a favorable orientation for Arg248 to interact with putative DNA, which is critically important to the sequence-specific DNA-binding activity of the p53DBD. However, the effect of Mg2+ is less marked. Additionally, analysis of the natural bond orbital (NBO) charge transfer reveals that Mg2+ has a higher net positive charge than Zn2+, leading to a stronger electrostatic attractive interaction between Mg2+ and putative DNA. This may partly explain the higher sequence-independent DNA-binding affinity of p53DBD–Mg2+ compared to p53DBD–Zn2+ observed in experiment.

Amphiphilic cholesteryl 2,6-di-O-methyl-β-cyclodextrins (chol-DIMEB) can self-aggregate into spherical micelles of noteworthy potential for drug delivery. All-atom molecular dynamics simulations of chol-DIMEB micelles consisting of 3−24 monomers have been performed in aqueous solution. chol-DIMEB exhibits a pronounced tendency to self-assemble into core−shell structures. van der Waals interactions within the cholesteryl nucleus constitute the main driving force responsible for the formation of the micelle. The calculated radii of the hydrophobic core and of the hydrophilic shell for the micellar structure formed by 24 monomers agree well with the experiment. The cyclodextrin moieties are found to be exposed toward the aqueous medium and possess the appropriate flexibility to capture drugs in an effective fashion. Analysis of the solvent accessible surface area and hydration number indicates that the micelles are highly hydrosoluble species and can, therefore, enhance significantly the aqueous solubility of lipophilic drugs. In addition, the spatial structure of the micelles is suggestive of multiple potential drug binding sites. The present contribution unveils how micelles endowed with specific characteristics can form, while opening exciting perspectives for the design of novel micellar nanoparticles envisioned to be drug carriers of high potential.

Carbon nanotubes wrapped by polysaccharide chains like chitosan (CHTS) or its derivatives through noncovalent decoration have been shown to condense effectively and deliver DNA for gene therapy. Despite the importance of these novel nanoscale materials, the detail of the microscopic structure and underlying interaction mechanism is still fragmentary. In the present work, the complex formed by CHTS and a single-walled carbon nanotube (SWNT) has been investigated by means of atomistic molecular dynamics (MD) simulations to explore its propensity toward self-assembly, together with its structural properties in an aqueous environment. The present results reveal that CHTS can wrap spontaneously the tubular surface by regulating backbone torsional stress upon van der Waals attraction by the SWNT, resulting in a steady, right-handed helical conformation. The free-energy landscape characterizing the wrapping process of the CHTS chain from a straight conformation to a tight helical one brings to light two energetically favored helical conformations corresponding to distinct pitches. In addition, the degree of deacetylation of the polysaccharide chain, but not the pH, induces pronounced fluctuations in the geometrical properties of the helix.

Carbon nanotubes coated with alginic acid (AA) through noncovalent functionalization have been shown to be soluble and dispersed in water. In the present contribution, all-atom molecular dynamics simulations have been performed to probe the self-assembly mechanism that underlies the formation of complexes by AA and a single-walled carbon nanotube (SWCNT), both in the gas phase and in an aqueous solution. Results of these simulations reveal that AA can wrap around SWCNT by virtue of van der Waals attractions and organize into a compact helical structure, a process induced in the gas phase by hydrogen-bonding interactions. In contrast, in an alginate aqueous solution, a loose helical wrapping mode is found to be favored by virtue of electrostatic repulsions in conjunction with the weakening of hydrogen-bonding interactions. Documented experimentally (Liu, Y.; et al. Small 2006, 2, 874−878) and coined “Great Wall of China” motif, the typical arrangement of AA residues around the tubular structure, conducive to dissolve nanotubes, is observed in the present simulations. Investigation of metal cations binding to AA suggests that calcium ions can mediate aggregation of AA chains by interacting strongly with the carboxylate groups, thereby leading to reverse unwrapping. The results reported in this work shed meaningful light on the potential of noncovalent functionalization for solubilizing carbon nanotubes, and open exciting perspectives for the design of new wrapping agents that are envisioned to form the basis of innovative nanomaterials targeted at chemical and biomedical applications.

A prototypical molecular shuttle formed by dodecamethylene and 4,4′-bipyridinium units and an α-cyclodextrin (CD) was investigated employing molecular dynamics simulations. The free-energy profile characterizing the shuttling process of the α-CD along the molecular thread was determined using the adaptive biasing force method, revealing two thermodynamically stable states separated by a pronounced energy barrier. The free-energy barrier with respect to the stable states is calculated to be +20.6 kcal/mol, in excellent agreement with the experimentally measured quantity. Partitioning of the free energy into contributions of different nature indicates that the shuttling process is primarily controlled by the favorable inclusion of the dodecamethylene chain and the unfavorable inclusion of the cationic bipyridinium group by α-CD. The predominant contribution to the energy barrier stems from the disruption of the solvation shell of the charged group. Deciphering the molecular mechanism of the shuttling process is expected to help design new controllable molecular shuttles.Keywords (keywords): cyclodextrins; free-energy calculations; molecular dynamics simulations; molecular shuttles; rotaxanes;

A systematic first-principle study based on the density functional theory has been performed on the electronic structures and stabilities of fullerene C68 and its derivatives C68X4 (X = H, F, Cl). By searching the 6332 classical and 43 nonclassical isomers of C68, the ground state is found to be the classical isomer 6290 bearing C2 symmetry. However, after attaching X atoms to the active sites of C68, the heptagon-containing nonclassical derivatives C68(c)-2 C68H4, C68(c)-2 C68F4, and C68(c)-3 C68Cl4 are predicted to be the most stable among all derivatives. The chemical deriving could affect the electronic structures distinctly, and enhance the stability of fullerene C68. The Mulliken charge populations of the most stable C68X4 are calculated, showing that different X atoms added to C68 will cause remarkably different charge populations. The IR, Raman, and NMR spectra of the most stable C68X4 are also calculated and presented to facilitate future experimental identification.

The properties of four finite-length bent and straight intramolecular junctions (IMJs) connecting two armchair and zigzag single-walled carbon nanotube segments, viz. (3,3)-(6,0) and (4,4)-(8,0), were investigated. Their structures were calculated using the density functional theory (DFT) methods at the B3LYP/6-31G(d) level of theory. The results indicate that the bent junctions are more stable than the straight ones due to the energetically favored defect structures. Remarkable differences of the HOMO and LUMO orbitals appear between the straight and the bent IMJs. The spin-unrestricted calculations at the same level of theory were also performed to obtain the antiferromagnetic-type ground state, suggesting that the spin polarizations mainly occur on the zigzag edge and the defect rings of the straight (4,4)-(8,0) IMJ and induce marked changes of the electronic structures. Additionally, the energy band structures of the four junctions with periodic boundary conditions were calculated based on DFT calculations using generalized gradient approximation with the Perdew and Wang function. The calculated band gaps suggest that the conductance of the straight IMJs is higher than the bent ones.

The inclusion of hydrocortisone, progesterone, and testosterone into the cavity of β-cyclodextrin (β-CD) following two possible orientations was investigated using molecular dynamics simulations and free-energy calculations. The free-energy profiles that delineate the inclusion process were determined using an adaptive biasing force. The present results reveal that although the free-energy surfaces feature two local minima corresponding to a partial and a complete inclusion, the former mode is markedly preferred, irrespective of the orientation. Ranking the propensity of the three steroidal molecules to associate with β-CD, viz. progesterone > testosterone > hydrocortisone, is shown to be in excellent agreement with experiment. This conclusion is further supported by independent calculations relying on alchemical transformations in conjunction with free energy perturbation, wherein the relative binding free energy for the three steroids was estimated. In addition, decomposition of the potentials of mean force into free-energy contributions and significant decrease in the total hydrophobic surface area suggest that by and large, van der Waals and hydrophobic interactions constitute the main driving forces responsible for the formation of the inclusion complexes. Analysis of their structural features from the molecular dynamics trajectories brings to light different hydrogen-bonding patterns that are characterized by distinct dynamics and stabilities.

The geometrical structures, electronic properties, and stabilities of the unconventional fullerene derivatives C64X6 (X = H, F, Cl) have been systematically studied by the first-principle calculations based on the density functional theory. The fullerene derivatives 1911(2)-C64X6 generated from the pineapple-shaped C64X4 are predicted to possess the lowest energies. The other two X atoms are added to the carbon atoms with the highest local strain assessed by the pyramidalization angles. The calculations of the nucleus-independent chemical shifts suggest that the aromaticity of C64X6 affects the stability order of the derivative isomers. To address why C64H6 was not observed in the experimental study of Wang et al. (J. Am. Chem. Soc. 2006, 128, 6605) and if the halogenated derivatives C64X6 (X = F, Cl) can be synthesized, thermochemical analysis of the reaction C64X4 + X2 → C64X6 was also performed. The results indicate that the formation of C64H6 and C64Cl6 is not favored at high temperatures. The former may be a reason why C64H6 was not found in the experiment. In sharp contrast, the Gibbs free energy change to form C64F6 is found to be −23.29 kcal/mol at 2000 K, suggesting that this compound may be formed and detected in experiments. The NMR and IR spectra of 1911(2)-C64F6 are sequentially calculated and presented to facilitate future experimental identification.

The well-documented anomalous solubility of β-cyclodextrin (β-CD), relative to α- and γ-CD, has been examined by Naidoo et al. (J. Phys. Chem. B, 2004, 108, 4236–4238.) from the perspective of water organization and internal motion of the macrocyclic rings. Whether modulation in the hydration patterns and in the rigidity of the molecular scaffold can be reconciled with the hydration free energy of β-CD to rationalize its notorious low solubility remains open to further investigation. In this contribution, multi-nanosecond molecular dynamics (MD) simulations have been carried out to investigate the hydration process of α-, β- and γ-CD. The distribution of water molecules involved in this process and the linearity of intramolecular hydrogen bonds have been analyzed. The results reported here demonstrate that the anomalous solubility for β-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility. The hydration free energy of α-, β- and γ-CD was computed using the free energy perturbation method. This quantity is shown to increase with the number of glucose units, thereby suggesting that the anomalous solubility of β-CD cannot be explained by its free energy of hydration alone.

SHEF (spherical harmonic coefficient filter), a geometrical matching procedure constituting a preliminary step in the virtual high throughput screening of large databases of small drug-like molecules, is demonstrated. This filter uses a description of both the binding site of the target and the ligand surfaces using spherical harmonic polynomial expansions. Using this representation, which is based on limited sets of spherical harmonic coefficients, considerably reduces the complexity of surface complementarity calculation. As a first test, 188 known protein–ligand complexes were used, and the results of docking the abstracted ligands into the bare proteins using SHEF were compared to the original X-ray structures. The ability of SHEF to retrieve known ligands “hidden” in a virtual library of 1,000 randomly selected drug-like compounds is also demonstrated.

Consensus modeling of combining the results of multiple independent models to produce a single prediction avoids the instability of single model. Based on the principle of consensus modeling, a consensus least squares support vector regression (LS-SVR) method for calibrating the near-infrared (NIR) spectra was proposed. In the proposed approach, NIR spectra of plant samples were firstly preprocessed using discrete wavelet transform (DWT) for filtering the spectral background and noise, then, consensus LS-SVR technique was used for building the calibration model. With an optimization of the parameters involved in the modeling, a satisfied model was achieved for predicting the content of reducing sugar in plant samples. The predicted results show that consensus LS-SVR model is more robust and reliable than the conventional partial least squares (PLS) and LS-SVR methods.

Are the semiempirical methods still reliable for large fullerenes? To answer this question, in this paper, the semiempirical AM1, PM3, MNDO, and tight-binding calculations were performed on the candidate isomers selected from the complete sets of isolated-pentagon-rule isomers of C116–C120 based on the second generation reactive empirical bond order potential. To assess the reliability of these semiempirical methods and predict the ground-state structures more accurately, the density functional theory calculations at the B3LYP/6-31G(d)//B3LYP/3-21G level of theory were also carried out on the top 20 low-energy candidates from each semiempirical method. It was found that the tight-binding potential gives a good agreement for the prediction of the relative energies when compared with the B3LYP/6-31G∗ results, while AM1, PM3, and MNDO methods behave badly. Furthermore, we also investigated the structures of the B3LYP/6-31G∗ low-energy isomers for C116–C120 to understand the relationship between the stability and some structural factors.

The well-documented anomalous solubility of β-cyclodextrin (β-CD), relative to α- and γ-CD, has been examined by Naidoo et al. (J. Phys. Chem. B, 2004, 108, 4236–4238.) from the perspective of water organization and internal motion of the macrocyclic rings. Whether modulation in the hydration patterns and in the rigidity of the molecular scaffold can be reconciled with the hydration free energy of β-CD to rationalize its notorious low solubility remains open to further investigation. In this contribution, multi-nanosecond molecular dynamics (MD) simulations have been carried out to investigate the hydration process of α-, β- and γ-CD. The distribution of water molecules involved in this process and the linearity of intramolecular hydrogen bonds have been analyzed. The results reported here demonstrate that the anomalous solubility for β-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility. The hydration free energy of α-, β- and γ-CD was computed using the free energy perturbation method. This quantity is shown to increase with the number of glucose units, thereby suggesting that the anomalous solubility of β-CD cannot be explained by its free energy of hydration alone.

Zn2+ in the tumor-suppressor protein p53 DNA-binding domain (DBD) is essential for its structural stability and DNA-binding specificity. Mg2+ has also been recently reported to bind to the p53DBD and influence its DNA-binding activity. In this contribution, the binding geometry of Mg2+ in the p53DBD and the mechanism of how Mg2+ affects its DNA-binding activity were investigated using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Various possible coordination geometries of Mg2+ binding to histidines (His), cysteines (Cys), and water molecules were studied at the B3LYP/6-311+g** level of theory. The protonation state of Cys and the environment were taken into account to explore the factors governing the coordination geometry. The free energy of the reaction to form the Mg2+ complexes was estimated, suggesting that the favorable binding mode changes from a four- to six-coordinated geometry as the number of the protonated Cys increases. Furthermore, MD simulations were employed to explore the binding modes of Mg2+ in the active site of the p53DBD. The simulation results of the Mg2+ system and the native Zn2+ system show that the binding affinity of Mg2+to the p53DBD is weaker than that of Zn2+, in agreement with the DFT calculation results and experiments. In addition, the two metal ions are found to make a significant contribution to maintain a favorable orientation for Arg248 to interact with putative DNA, which is critically important to the sequence-specific DNA-binding activity of the p53DBD. However, the effect of Mg2+ is less marked. Additionally, analysis of the natural bond orbital (NBO) charge transfer reveals that Mg2+ has a higher net positive charge than Zn2+, leading to a stronger electrostatic attractive interaction between Mg2+ and putative DNA. This may partly explain the higher sequence-independent DNA-binding affinity of p53DBD–Mg2+ compared to p53DBD–Zn2+ observed in experiment.

Binding of cucurbit[6]uril (CB[6]) with the hexamethylene diammonium cation (HD2+) in the presence of sodium ions is elucidated at the atomic level. The most probable complex of CB[6] in saline solution is found to be CB[6]:Na+. A two-stage binding process of CB[6]:Na+ with HD2+ is proposed.

Disentangling the different movements observed in rotaxanes is critical to characterize their function as molecular and biological motors. How to achieve unidirectional rotation is an important question for successful construction of a highly efficient molecular motor. The motions within a rotaxane composed of a benzylic amide ring threaded on a fumaramide moiety were investigated employing atomistic molecular dynamics simulations. The free-energy profiles describing the rotational process of the ring about the thread were determined from multi-microsecond simulations. Comparing the theoretical free-energy barriers with their experimental counterpart, the syn–anti isomerization of the amide bond within the ring was ruled out. The free-energy barriers arise in fact from the disruption of hydrogen bonds between the ring and the thread. Transition path analysis reveals that complete description of the reaction coordinate requires another collective variable. The free-energy landscape spanned by the two variables characterizing the coupled rotational and shuttling processes of the ring in the rotaxane was mapped. The calculated free-energy barrier, amounting to 9.3 kcal mol−1, agrees well with experiment. Further analysis shows that shuttling is coupled with the isomerization of the ring, which is not limited to a simplistic chair-to-chair transition. This work provides a cogent example that contrary to chemical intuition, molecular motion can result from complex, entangled movements requiring for their accurate description careful modeling of the underlying reaction coordinate. The methodology described here can be used to evaluate the different components of the multifaceted motion in rotaxanes, and constitutes a robust tool for the rational design of molecular machines.

We have investigated at the atomic level amide-based rotaxanes set in motion in four different solvents, namely, ethyl ether, acetonitrile, ethanol and water. In three non-aqueous solvents, shuttling of the macrocycle between two binding sites separated by a free-energy barrier is coupled with a conformational change and rotation, driven primarily by hydrogen-bonding interactions. The mechanism that underlies the shuttling is completely altered when the non-aqueous solvent is replaced by water. In aqueous solution, hydrophobic interactions chiefly control shuttling of the rotaxane, leading to a sharp decrease of the free-energy barrier, thereby speeding up the process. The binding sites and the reaction pathway describing shuttling vary significantly in water compared with in the other three solvents. We found that the high polarity, the hydrogen-bond donor and acceptor ability, and the minimal steric hindrance of water conspire to modify the mechanism. These three physicochemical properties are also responsible for the lubrication by water. That water completely changes the mechanism underlying the shuttling of rotaxanes, is addressed for the first time in this study, and provides valuable guidelines for the de novo design of molecular machines.