Van Der Waals Energy Research Articles

Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease.

3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (Mutant(Bound)) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, R(g) and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on the ligand (3CPI). The double mutations triggered a distortion orientation of 3CPI in the active site and decreases the binding energy, ΔG(bind) (∼3 kcal mol(-1)), compared to the wild type (Wild(Bound)). The van der Waals and electrostatic energy contributions coming from residues 68 and 126 are lower for Mutant(Bound) when compared with Wild(Bound). In addition, variation in the overall enzyme motion as evident from the PCA, distorted hydrogen bonding network and loss of protein-ligand interactions resulted in a loss of inhibitor efficiency. The comprehensive molecular insight gained from this study should be of great importance in understanding the drug resistance against CVB3 3C protease; also, it will assist in the designing of novel Coxsackievirus B3 inhibitors with high ligand efficacy on resistant strains.

Probing the binding mechanism of Mnk inhibitors by docking and molecular dynamics simulations.

Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar to micromolar range. In the current work we model the inhibition of Mnk kinase activity by these inhibitors using various computational approaches. Combining homology modeling, docking, molecular dynamics simulations, and free energy calculations, we find that all compounds bind similarly to the active sites of both kinases with their imidazopyridine and imidazopyrazine cores anchored to the hinge regions of the kinases through hydrogen bonds. In addition, hydrogen bond interactions between the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131 (Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability of the bound conformations of the inhibitors. The computed binding free energies (ΔGPred) of these inhibitors are in accord with experimental bioactivity data (pIC50) with correlation coefficients (r(2)) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals energies and entropic effects appear to dominate the binding free energy (ΔGPred) for each Mnk-inhibitor complex studied. The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues.

A mechanophysical phase transition provides a dramatic example of colour polymorphism: the tribochromism of a substituted tri(methylene)tetrahydrofuran-2-one.

BackgroundDerivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed “tribochromism”. We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies.ResultsA number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2-one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb – which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb.ConclusionsOur studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice.Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-014-0070-3) contains supplementary material, which is available to authorized users.

Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53–0.65) and fitted correlation r2 (0.82–0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

Creep–Fatigue Relationship in Polymer: Molecular Dynamics Simulations Approach

The creep‐tensile fatigue relationship is investigated using MD simulations for amorphous polyethylene, by stepwise increasing the R‐ratio from 0.3 for fatigue to an R‐ratio = 1 for creep. The simulations can produce similar behavior as observed in experiments, for instances strain‐softening behavior and hysteresis loops in the stress‐strain curves. The simulations predict the molecular mechanisms of creep and fatigue are the same. Fatigue and creep cause significant changes of the van der Waals and dihedral potential energies. These changes are caused by movements of the polymer chains, creating more un‐twisted dihedral angles and the unfolding of polymer chains along the loading direction.

Chiral recognition of Propranolol enantiomers by β-Cyclodextrin: Quantum chemical calculation and molecular dynamics simulation studies

Enantiomeric recognition of Propranolol by complexation with β-Cyclodextrin was studied by PM3 method and molecular dynamics (MD) simulation. Gas phase results show that the R-enantiomer complex is more stable than the S-enantiomer complex by 8.54kJ/mol (Hartree–Fock energy). Using polarized continuum model, solution phase of R-enantiomer complex was found to be more stable than S-enantiomer complex by 25.95kJ/mol. Both complexes hardly occur at room temperature free-energy-wise, though, complexation with R-enantiomer is more favorable than with S-enantiomer enthalpy-wise.Also, complexes were studied by molecular dynamics simulation in gas and solution phases. More stability of R-enantiomer complex in gas phase is confirmed by MD van der Waals energy (5.04kJ/mol) and closely by the counterpart PM3 binding energy (8.54kJ/mol). Simulation in solution phase indicates more stability of R-enantiomer complex. Finally, simulated transport property provides insight into the high anisotropic atoms motion according to which S-Propranolol found possessing significantly higher dynamics.

Influence of Cohesive Energy and Chain Stiffness on Polymer Glass Formation

The generalized entropy theory is applied to assess the joint influence of the microscopic cohesive energy and chain stiffness on glass formation in polymer melts using a minimal model containing a single bending energy and a single (monomer averaged) nearest neighbor van der Waals energy. The analysis focuses on the combined impact of the microscopic cohesive energy and chain stiffness on the magnitudes of the isobaric fragility parameter mP and the glass transition temperature Tg. The computations imply that polymers with rigid structures and weak nearest neighbor interactions are the most fragile, while Tg becomes larger when the chains are stiffer and/or nearest neighbor interactions are stronger. Two simple fitting formulas summarize the computations describing the dependence of mP and Tg on the microscopic cohesive and bending energies. The consideration of the combined influence of the microscopic cohesive and bending energies leads to the identification of some important design concepts, such as iso-fragility and iso-Tg lines, where, for instance, iso-fragility lines are contours with constant mP but variable Tg. Several thermodynamic properties are found to remain invariant along the iso-fragility lines, while no special characteristics are detected along the iso-Tg lines. Our analysis supports the widely held view that fragility provides more fundamental insight for the description of glass formation than Tg.

Efficient Maintenance and Update of Nonbonded Lists in Macromolecular Simulations.

Molecular mechanics and dynamics simulations use distance based cutoff approximations for faster computation of pairwise van der Waals and electrostatic energy terms. These approximations traditionally use a precalculated and periodically updated list of interacting atom pairs, known as the “nonbonded neighborhood lists” or nblists, in order to reduce the overhead of finding atom pairs that are within distance cutoff. The size of nblists grows linearly with the number of atoms in the system and superlinearly with the distance cutoff, and as a result, they require significant amount of memory for large molecular systems. The high space usage leads to poor cache performance, which slows computation for large distance cutoffs. Also, the high cost of updates means that one cannot afford to keep the data structure always synchronized with the configuration of the molecules when efficiency is at stake. We propose a dynamic octree data structure for implicit maintenance of nblists using space linear in the number of atoms but independent of the distance cutoff. The list can be updated very efficiently as the coordinates of atoms change during the simulation. Unlike explicit nblists, a single octree works for all distance cutoffs. In addition, octree is a cache-friendly data structure, and hence, it is less prone to cache miss slowdowns on modern memory hierarchies than nblists. Octrees use almost 2 orders of magnitude less memory, which is crucial for simulation of large systems, and while they are comparable in performance to nblists when the distance cutoff is small, they outperform nblists for larger systems and large cutoffs. Our tests show that octree implementation is approximately 1.5 times faster in practical use case scenarios as compared to nblists.

Multilayer graphene, Moiré patterns, grain boundaries and defects identified by scanning tunneling microscopy on the m-plane, non-polar surface of SiC

Epitaxial graphene is grown on a non-polar n+ 6H-SiC m-plane substrate and studied using atomic scale scanning tunneling microscopy. Multilayer graphene is found throughout the surface and exhibits rotational disorder. Moiré patterns of different spatial periodicities are found, and we found that as the wavelength increases, so does the amplitude of the modulations. This relationship reveals information about the interplay between the energy required to bend graphene and the interaction energy, i.e. van der Waals energy, with the graphene layer below. Our experiments are supported by theoretical calculations which predict that the membrane topographical amplitude scales with the Moiré pattern wavelength, L as L-1+αL-2.

Bonding in Group 1 Citrate Salts

Computational studies of > 15 new crystal structures and the 10 previously-reported structures of alkali metal citrates provide insight into why the atoms are where they are. The metal-citrate bonding is predominantly ionic, with very little covalent character, which decreases as the cation size increases. Bond valence calculations indicate that most cations are crowded, and that the crowding decreases as the cation size increases. Although most oxygen atoms coordinate to the metals, a few do not, and they tend to be the least-negative oxygens. Both the citrate hydroxyl groups and water molecules tend to bridge two cations, and the carboxylate coordination is more varied. The solid state energy differences are dominated by differences in van der Waals and electrostatic energy contributions. In the Li and Na salts, the citrate anion occurs predominantly in a higher-energy "kinked" conformation, rather than the extended lowest-energy conformation observed in salts of the larger cations. Detailed conformational analysis of the citrate anions enables quantification of the conformational energy costs in these solids. Hydrogen bonding is important to the stability of these salts. The Mulliken overlap population in the hydrogen bonds provides a quantitative measure of their strength, and permits identification of long (weak) interactions which are significant in some of these compounds. Patterns in both the local environments of the hydrogen bonds and the more-extended features (graph sets) are noted. Polymorphs and sets of isostructural compounds permit more-detailed analysis of the structures and energetics in these compounds. The order of ionization of the three carboxylic acid groups is in general central/terminal/terminal, but there are two exceptions. While we have concentrated on salts containing a single alkali metal cation (and hydrogen), the structures of NaK2C6H5O7 and NaKHC6H5O7 provide an exciting window on a larger universe of mixed salts.

Lattice cluster theory for polymer melts with specific interactions.

Despite the long-recognized fact that chemical structure and specific interactions greatly influence the thermodynamic properties of polymer systems, a predictive molecular theory that enables systematically addressing the role of chemical structure and specific interactions has been slow to develop even for polymer melts. While the lattice cluster theory (LCT) provides a powerful vehicle for understanding the influence of various molecular factors, such as monomer structure, on the thermodynamic properties of polymer melts and blends, the application of the LCT has heretofore been limited to the use of the simplest polymer model in which all united atom groups within the monomers of a species interact with a common monomer averaged van der Waals energy. Thus, the description of a compressible polymer melt involves a single van der Waals energy. As a first step towards developing more realistic descriptions to aid in the analysis of experimental data and the design of new materials, the LCT is extended here to treat models of polymer melts in which the backbone and side groups have different interaction strengths, so three energy parameters are present, namely, backbone-backbone, side group-side group, and backbone-side group interaction energies. Because of the great algebraic complexity of this extension, we retain maximal simplicity within this class of models by further specializing this initial study to models of polymer melts comprising chains with poly(n-α-olefin) structures where only the end segments on the side chains may have different, specific van der Waals interaction energies with the other united atom groups. An analytical expression for the LCT Helmholtz free energy is derived for the new model. Illustrative calculations are presented to demonstrate the degree to which the thermodynamic properties of polymer melts can be controlled by specific interactions.

Modulating the electronic structure of chromophores by chemical substituents for efficient energy transfer: application to fluorone.

Strong electron correlation within a quasi-spin model of chromophores was recently shown to enhance exciton energy transfer significantly. Here we investigate how the modulation of the electronic structure of the chromophores by chemical substitution can enhance energy-transfer efficiency. Unlike previous work that does not consider the direct effect of the electronic structure on exciton dynamics, we add chemical substituents to the fluorone dimer to study the effect of electron-donating and electron-withdrawing substituents on exciton energy transfer. The exciton dynamics are studied from the solution of a quantum Liouville equation for an open system whose model Hamiltonian is derived from excited-state electronic structure calculations. Both van der Waals energies and coupling energies, arising from the Hellmann-Feynman force generated upon transferring the dimers from infinity to a finite separation, are built into the model Hamiltonian. Though these two effects are implicitly treated in dipole-based models, their explicit and separate treatment as discussed here is critical to forging the correct connection with the electronic structure calculations. We find that the addition of electron-donating substituents to the fluorone system results in an increase in exciton-transfer rates by factors ranging from 1.3-1.9. The computed oscillator strength is consistent with the recent experimental results on a larger heterodimer system containing fluorone. The oscillator strength increases with the addition of electron-donating substituents. Our results indicate that the study of chromophore networks via electronic structure will help in the future design of efficient synthetic light-harvesting systems.

Computational and statistical study on the molecular interaction between antigen and antibody

Monoclonal antibodies are one of the most successful bio-molecules utilized in the clinical scene of today. It is important to clarify general characteristics of the interaction between antigen and antibody and to draw a guide for enhancing their binding affinity in rational design of antibody drugs. In this study, we carried out molecular dynamics simulations for 20 kinds of antigen–antibody complexes. From the statistical analysis of the calculation results, the following findings were deduced. At complementarity determining regions (CDRs) of the antibodies, the rates for the presence of serine (Ser) and tyrosine (Tyr) are high. The amino residues involved in direct hydrogen bonds between antigens and antibodies were examined by counting the numbers of the hydrogen bonds from the respective residues. The contribution of Tyr to the direct hydrogen bonding was the highest and that of Ser was the fourth. Furthermore, the short-distance hydrogen bonds, which is assumed to be so-called “low-barrier hydrogen bond”, were observed at CDRs in three complexes. Interestingly, Ser is involved in the short-distance hydrogen bonding in two cases out of the three. This result suggests that these two unchanged polar amino acid residues play an important role for recognition of antigen. In almost all of the complexes (18/20), the contribution of the electrostatic energy (ΔEele) to the binding free energy was calculated to be larger than that of the van der Waals energy (ΔEvdw). This dominance of the electrostatic energy is in contrast to the case that low molecular-weight compounds are bound to their targets. The findings of this study will be helpful to design an antibody with a high specificity and a high affinity to the antigen.

Identification of Important Residues by Computational Alanine Scanning Analysis of Interaction Mechanisms of scFv Anti-p17 Complexes Based on Molecular Dynamics Simulations

Molecular dynamics simulation (MD) coupled with molecular mechanics generalized Born surface area (MM-GBSA) method were performed to probe the binding mechanisms of single chain Fv fragment with p17 epitopes of HIV-1 protease (scFv anti-p17). The results show that van der Waals and electrostatic energy is a main force of the binding. Computational alanine scanning by substitution of the amino acids in binding to alanine and analysis of structure-affinity relation were used to predict the antibody-antigen binding modes. The important residues locate in the hot spot of the surface between scFv and p17 have been identified. This study can contribute significantly to the designs of the novel antibody targeting the p17 peptides. Point mutations and molecular docking between the modeled scFv antibody and p17 peptides have been investigated in some of the key residues to search for novel antibody with the improved binding activity. The experimental results have been compared to see how well of the prediction.

Dissecting the Critical Factors for Thermodynamic Stability of Modular Proteins Using Molecular Modeling Approach

Repeat proteins have recently attracted much attention as alternative scaffolds to immunoglobulin antibodies due to their unique structural and biophysical features. In particular, repeat proteins show high stability against temperature and chaotic agents. Despite many studies, structural features for the stability of repeat proteins remain poorly understood. Here we present an interesting result from in silico analyses pursuing the factors which affect the stability of repeat proteins. Previously developed repebody structure based on variable lymphocytes receptors (VLRs) which consists of leucine-rich repeat (LRR) modules was used as initial structure for the present study. We constructed extra six repebody structures with varying numbers of repeat modules and those structures were used for molecular dynamics simulations. For the structures, the intramolecular interactions including backbone H-bonds, van der Waals energy, and hydrophobicity were investigated and then the radius of gyration, solvent-accessible surface area, ratio of secondary structure, and hydration free energy were also calculated to find out the relationship between the number of LRR modules and stability of the protein. Our results show that the intramolecular interactions lead to more compact structure and smaller surface area of the repebodies, which are critical for the stability of repeat proteins. The other features were also well compatible with the experimental results. Based on our observations, the repebody-5 was proposed as the best structure from the all repebodies in structure optimization process. The present study successfully demonstrated that our computer-based molecular modeling approach can significantly contribute to the experiment-based protein engineering challenge.

RETRACTED: Mixed mode peeling of spinnable carbon nanotube webs

This paper presents the study on interaction behaviour of spinnable carbon nanotubes by the peel test technique. Spinnable nanotube webs are used as macro scale experimental specimens to determine the mixed mode interaction behaviour between them. Numerical simulations are conducted to determine and compare the interfacial fracture energy of the interfaces in different orientations peeled at the same peel angle. The numerical model simulates the Van der Waals energy between nanotube webs through implementation of a cohesive law. The peeling process is simulated by considering a failure criterion based on continuum damage mechanics. It is shown that the interfacial energy varied with the orientation angle and the peel angle. Interfacial energy for parallel nanotube configuration is much higher than the crossed nanotube configuration. Increase in peel angle reduces the phase angle magnitudes so that the loading condition transforms from mode – II to mode – I resulting into reduction of the forces required to detach spinnable nanotubes. Hence, this study explores the spinnable nanotube interaction mechanics through which slippage may easily occur among them. Thus, the reason behind nanotube yarn failure before reaching large macroscopic stresses is better understood even though individual spinnable nanotube found to be very strong.

Peel test of spinnable carbon nanotube webs

This paper presents results of peel tests with spinnable carbon nanotube webs. Peel tests were performed to study the effect of orientation angles on interface energies between nanotubes. In absence of any binding agent the interface energy represents the Van Der Waals energies between the interacting nanotubes. Therefore, the effect of the orientations on Van Der Waals energies between carbon nanotubes is obtained through the peel test. It is shown that the energy for crossed nanotubes at 90° angle is lower than the energy for parallel nanotubes at 0° angle. This experimental observation was validated by hypothetical theoretical calculations.

Salting‐out thin‐layer chromatography and computational analysis of some oral hypoglycemic drugs

A quantitative structure-retention relationship study of some oral hypoglycemic drugs was carried out using a salting-out thin-layer chromatographic technique. Aqueous solution of ammonium sulfate and acetonitrile was used as a mobile phase. It was established that the applied mobile phase has different effects on retention of the studied oral antidiabetic drugs. The factors that affect the salting-out process were determined. In this study a good correlation between the structures of the investigated drugs with the retention data and molecular descriptors was established throughout computational analysis and using molecular operating environment software, focusing on octanol/water partition coefficient, molar refractivity, total hydrophobic surface area, hydrophobic volume, Van der Waals energy and solvation energy. Quantitative structure-retention relationship modeling for the separation of the investigated drugs was carried out, validated and evaluated.

Plasmonic and Energy Studies of Ag Nanoparticles in Silica-Titania Hosts

The present work reports an investigation of surface plasmon resonance (SPR) of silver nanoparticles in SiO2-TiO2 hosts. The surface plasmon resonance of silver nanoparticles was observed in the wavelength range 300-400 nm. Numerical calculation of SPR of silver nanoparticles with spherical morphology was done on the basis of discrete dipole approximation (DDA) method. The observed fluorescence spectrum fits well with the theoretically calculated one. The luminescence enhancement is attributed to the strong local electric field which increases the exciting and emitting photons coupled to SPR. An effort has been made to study the surface plasmon mediated excitation energy transfer (EET) between two spherical metal nanoparticles. The van der Waals (vdW) energy between plasmonic silver nanoparticles in the present hosts has been estimated.

Graphene on boron-nitride: Moiré pattern in the van der Waals energy

The spatial dependence of the van der Waals (vdW) energy between graphene and hexagonal boron-nitride (h-BN) is investigated using atomistic simulations. The van der Waals energy between graphene and h-BN shows a hexagonal superlattice structure identical to the observed Moiré pattern in the local density of states, which depends on the lattice mismatch and misorientation angle between graphene and h-BN. Our results provide atomistic features of the weak van der Waals interaction between graphene and BN which are in agreement with experiment and provide an analytical expression for the size of the spatial variation of the weak van der Waals interaction. We also found that the A-B-lattice symmetry of graphene is broken along the armchair direction.