Comparative Molecular Dynamics Study Research Articles

Direct observation of the substitution effects on the hydrogen bridge dynamics in selected Schiff bases—A comparative molecular dynamics study

We have studied substituent effects on the properties of the intramolecular hydrogen bond of some ortho-hydroxy Schiff bases using density functional theory (DFT) based first-principle molecular dynamics (FPMD) and path integral molecular dynamics. The studied compounds possess a strong intramolecular hydrogen bond (r((O⋅⋅⋅N)) ≤ 2.6 Å), which can be tuned by substitution to either (i) enhance the basicity of the acceptor moiety by induction effects or (ii) decrease the hydrogen bond length through steric repulsion. DFT calculations and FPMD were employed to investigate structural and dynamical properties of the selected molecules, while quantum effects on the structural properties were assessed using path integral FPMD. The simulations were performed in vacuo and in the solid state to study the influence of the environment on the hydrogen bond and spectroscopic properties. We give computational support to the suggestion that induction effects are less effective to tune the intramolecular hydrogen bond properties of the discussed ortho-hydroxy Schiff bases than the steric or the environmental effects.

Interaction of the disaccharides trehalose and gentiobiose with lipid bilayers: A comparative molecular dynamics study

Abstract The disaccharide α, α-trehalose (TRH) is known for its bioprotective action in organisms subject to stressful environmental conditions. However, the mechanisms whereby TRH stabilizes biomolecules remains matter of debate, the five main hypotheses being the water replacement (WRH), headgroup bridging (HBH), vitrification (VIH), water entrapment (WEH) and hydration forces (HFH) hypotheses. Four hypotheses (all except HFH) are in principle compatible with a preferential affinity of the sugar molecules (compared to water) for the biomolecular surface. According to the recently proposed sugar-like mechanism (Pereira and Hünenberger [29]), preferential affinity would result from the entropy gain upon releasing many water molecules from the surface region to the bulk, at the cost of immobilizing and rigidifying fewer sugar molecules. Thus, a more flexible disaccharide such as gentiobiose (GNT) should evidence a weaker preferential affinity, limiting its bioprotective ability. In this work, molecular dynamics (MD) simulations of a dipalmitoyl-phosphatidylcholine (DPPC) bilayer patch in the presence of either pure water or aqueous solutions of GNT or TRH are performed in order to assess the validity of this suggestion. At 475 K and 1.6 m (molal), TRH indeed preserves the bilayer structure to a larger extent compared to GNT. However, the present investigation does not unambiguously indicate which of the above mechanism takes place, since the simulations reveal characteristic features of all of them. This suggests either that multiple mechanisms may be simultaneously active or that their definitions are not precise enough.

Interaction of alginate single-chain polyguluronate segments with mono- and divalent metal cations: a comparative molecular dynamics study

The interaction of a set of monovalent (Na+, K+) and divalent (Mg2+, Ca2+) metal cations with single-chain polyguluronate (periodic chain based on a dodecameric repeat unit, 21-helical conformation) is investigated using explicit-solvent molecular dynamics simulations (at 300 K and 1 bar). A total of 14 (neutralising) combinations of the different ions are considered (single type of cation or simultaneous presence of two types of cation, either in the presence or absence of chloride anions). The main observations are: (1) the chain conformation and intramolecular hydrogen bonding is insensitive to the counter-ion environment; (2) the binding of the cations is essentially non-specific for all ions considered (counter-ion atmosphere confined within a cylinder of high ionic density, but no well-defined binding sites); (3) the density and tightness of the distributions of the different cations within the counter-ion atmosphere follow the approximate sequence Ca2+>Mg2+>K+∼Na+; (4) the solvent-separated binding of the cations to the carboxylate groups of the chain is frequent, and its occurrence follows the approximate sequence K+>Na+>Ca2+>Mg2+ (contact-binding events as well as the binding of a cation to multiple carboxylate groups are very infrequent); and (5) the counter-ion atmosphere typically leads to a complete screening of the chain charge within 1.0–1.2 nm of the chain axis and, for most systems, to a charge reversal at about 1.5 nm (i.e. the effective chain charge becomes positive at this distance and as high in magnitude as one-quarter of the bare chain charge, before slowly decreasing to zero). These findings agree well (in a qualitative sense) with available experimental data and predictions from simple analytical models, and provide further insight concerning the nature of alginate–cation interactions in aqueous solution.

A comparative Molecular Dynamics study of water–methanol and acetone–methanol mixtures

Two binary mixtures with methanol as common component, namely water–methanol and methanol–acetone are studied by Molecular Dynamics simulations. Thermodynamical properties such as enthalpies, excess enthalpies, volumes and excess volumes are compared. Structural properties are studied through the various site–site pair correlation functions and the associated Kirkwood–Buff integrals. While the thermodynamical properties are relatively well calculated, we show that structural properties are affected by two severe problems. The first is an inherent property of the asymptote of the correlation function in finite systems, which affects their integrals, the second is the micro-heterogeneous structure of these hydrogen bonding mixtures, which affects the medium-to-long-range part of the distribution functions. These two problems conspire to make computer simulation unreliable to study this precise part of the structural properties of such mixtures. We propose pathways to correct this situation and demonstrate how it serves to considerably improve the calculated Kirkwood–Buff Integrals. Finally, we compare the two mixtures relative to their tendencies to form local heterogeneity. The analysis demonstrates that the micro-structure of neat methanol is better preserved in acetone than in water.

Probing Interaction Requirements in PTP1B Inhibitors: A Comparative Molecular Dynamics Study

Molecular dynamics studies were performed on eight different crystal structure complexes of protein tyrosine phosphatase 1B (PTP1B) to study energy components and interactions important for the binding of substrates/inhibitors. Calculation of the binding free energy and the different components was accomplished using molecular mechanics--Poisson-Boltzmann surface area and--generalized Born surface area methods. Free energy was decomposed into individual amino acid contribution to know the relative importance. Hydrogen-bond existence maps for individual ligands were monitored comprehensively. It is evident from flexibility studies that the complexes exhibit rigidity in WPD loop, which is the first prerequisite for PTP1B inhibition. The study suggests that for designing active site inhibitors, there should be an optimum balance between total electrostatic and van der Waals interactions. It is also established that for allosteric inhibitors, van der Waals interactions are significant in addition to electrostatic interactions that are responsible for strong binding affinity.

Dynamics based alignment of proteins: an alternative approach to quantify dynamic similarity

BackgroundThe dynamic motions of many proteins are central to their function. It therefore follows that the dynamic requirements of a protein are evolutionary constrained. In order to assess and quantify this, one needs to compare the dynamic motions of different proteins. Comparing the dynamics of distinct proteins may also provide insight into how protein motions are modified by variations in sequence and, consequently, by structure. The optimal way of comparing complex molecular motions is, however, far from trivial. The majority of comparative molecular dynamics studies performed to date relied upon prior sequence or structural alignment to define which residues were equivalent in 3-dimensional space.ResultsHere we discuss an alternative methodology for comparative molecular dynamics that does not require any prior alignment information. We show it is possible to align proteins based solely on their dynamics and that we can use these dynamics-based alignments to quantify the dynamic similarity of proteins. Our method was tested on 10 representative members of the PDZ domain family.ConclusionsAs a result of creating pair-wise dynamics-based alignments of PDZ domains, we have found evolutionarily conserved patterns in their backbone dynamics. The dynamic similarity of PDZ domains is highly correlated with their structural similarity as calculated with Dali. However, significant differences in their dynamics can be detected indicating that sequence has a more refined role to play in protein dynamics than just dictating the overall fold. We suggest that the method should be generally applicable.

Molecular defects of the glycine 41 variants of alanine glyoxylate aminotransferase associated with primary hyperoxaluria type I

G41 is an interfacial residue located within the alpha-helix 34-42 of alanine:glyoxylate aminotransferase (AGT). Its mutations on the major (AGT-Ma) or the minor (AGT-Mi) allele give rise to the variants G41R-Ma, G41R-Mi, and G41V-Ma causing hyperoxaluria type 1. Impairment of dimerization in these variants has been suggested to be responsible for immunoreactivity deficiency, intraperoxisomal aggregation, and sensitivity to proteasomal degradation. However, no experimental evidence supports this view. Here we report that G41 mutations, besides increasing the dimer-monomer equilibrium dissociation constant, affect the protein conformation and stability, and perturb its active site. As compared to AGT-Ma or AGT-Mi, G41 variants display different near-UV CD and intrinsic emission fluorescence spectra, larger exposure of hydrophobic surfaces, sensitivity to Met53-Tyr54 peptide bond cleavage by proteinase K, decreased thermostability, reduced coenzyme binding affinity, and catalytic efficiency. Additionally, unlike AGT-Ma and AGT-Mi, G41 variants under physiological conditions form insoluble inactive high-order aggregates (approximately 5,000 nm) through intermolecular electrostatic interactions. A comparative molecular dynamics study of the putative structures of AGT-Mi and G41R-Mi predicts that G41 --> R mutation causes a partial unwinding of the 34-42 alpha-helix and a displacement of the first 44 N-terminal residues including the active site loop 24-32. These simulations help us to envisage the possible structural basis of AGT dysfunction associated with G41 mutations. The detailed insight into how G41 mutations act on the structure-function of AGT may contribute to achieve the ultimate goal of correcting the effects of these mutations.

Comparative molecular dynamics study of the structural properties of melittin in water and trifluoroethanol/water

The structural properties and dynamic behavior of the antimicrobial peptide melittin in hydrophobic and polar environments have been investigated. The main characteristics of the secondary structure of melittin in different media have been analyzed and compared with the data on an ideal α-helix. It has been shown that melittin is an α-helix bent in the region of Pro14; the N-terminus of the peptide tends to unfold, while the C-terminal segment (residues 14–23) retains a helical structure for 20 ns of the simulation. 2,2,2-Trifluoroethanol molecules stabilize the helical structure of the peptide by lowering the dielectric constant of the environment and preferentially accumulating near particular sites of the polypeptide chain.

Crystal Structure, Absolute Configuration, Conformational Analysis and Molecular Dynamics Study of the Novel Steroidal Tetrazole Derivative: (25R)-3,12a-diaza-A,C-bishomo-5α-spirostano[3,4-d] [12a,12d] bistetrazole [HS-989

The X-ray crystal structure of the bistetrazole steroid derivative: (25R)-3,12a-diaza-A,C-bishomo-5α-spirostano[3,4-d] [12a,12d] bistetrazole (HS-989) has been determined at room temperature. The crystals are orthorhombic, space group P212121 with a = 16.855(1) A, b = 25.048(2) A, c = 6.402(1) A, V = 2702.7(5) A3 Z = 4, Density (calculated) = 1.250 Mg/m3. The tetrazole-modified 7-membered rings A and C have similar modified uniaxial chair conformations, with pseudo-symmetry m through the extra C–N tetrazole bond; the 6-membered rings B and F are symmetrical chairs; of the 5-membered rings, D is in a half-chair and ring E an envelope conformation; tetrazole rings T1 and T2 are both planar and oriented towards the α-face. The spirostan moiety is β-oriented. Overall the modified steroid skeleton is reasonably flat, with a pseudo-torsion angle C(19)–C(10)···C(13)–C(18) of −6.2°. Conformational sampling, using high temperature SYBYL molecular dynamics was used to investigate different arrangements of the steroid skeleton. Predicted low energy conformations were found to compare favourably in some respects with both X-ray crystallographic and NMR observations but with important differences. Determination of the crystal structure and absolute configuration of the novel steroidal tetrazole derivative (25R)-3,12a-diaza-A, C-bishomo-5α-spirostano[3,4-d] [12a 12d] bistetrazole [HS-989] are reported. The report includes a detailed conformational analysis and comparative molecular dynamics study.

Mechanism of Glycan Receptor Recognition and Specificity Switch for Avian, Swine and Human Adapted Influenza Virus Hemagglutinins: A Molecular Dynamics Perspective

Hemagglutinins (HA's) from duck, swine and human influenza viruses have previously been shown to prefer avian and human glycan receptor analogues with distinct topological profiles, pentasaccharides LSTa (α-2,3 linkage) and LSTc (α-2,6 linkage), in comparative molecular dynamics studies. Based upon detailed analyses of the dynamic motions of the receptor binding domains (RBD's) and interaction energy profiles with individual glycan residues, we have identified approximately 30 residue positions and secondary structural elements (SSE's) in the RBD that present distinct profiles with the receptor analogues. Glycan binding constrained the conformational space sampling by the HA. Electrostatic steering appeared to play a key role in glycan binding specificity. The complex dynamic behaviors of the major SSE and trimeric interfaces with or without bound glycans suggested that networks of interactions might account for species specificity in these low affinity and high avidity (multivalent) interactions between different HA and glycans. Contact frequency, energetic decomposition and H-bond analyses revealed species-specific differences in HA-glycan interaction profiles, not readily discernable from crystal structures alone. Interaction energy profiles indicated that mutation events at the set of residues such as 145, 156, 158 and 222 would favor human or avian receptor analogues, often through interactions with distal asialo-residues. These results correlate well with existing experimental evidence, and suggest new opportunities for simulation-based vaccine and drug development.

Protein Similarity Derived Solely from Molecular Dynamics

The dynamic motions of many proteins are central to their function. It therefore follows that the dynamic requirements of a protein are evolutionary constrained. In order to assess and quantify this, one needs to compare the dynamic motions of different proteins. Comparing the dynamics of distinct proteins may also provide insight into how protein motions are modified by variations in sequence and, consequently, by structure. The optimal way of comparing complex molecular motions is, however, far from trivial. The majority of comparative molecular dynamics studies performed to date relied upon prior sequence or structural alignment to define which residues were equivalent in 3-dimensional space. Here we discuss an alternative methodology for comparative molecular dynamics that does not require any prior alignment information. We show it is possible to align proteins based solely on their dynamics and that we can use these dynamics-based alignments to quantify the dynamic similarity of proteins. Our method was tested on 10 representative members of the PDZ domain family. As a result of creating pairwise dynamics-based alignments of PDZ domains, we have found evolutionarily conserved patterns in their backbone dynamics. We compare the results to other recently developed methods.

Comparative Molecular Dynamics Study of Aβ Adsorption on the Self-Assembled Monolayers

The adsorption and aggregation of the amyloid-beta (Abeta) peptides on the cell membrane plays a causal role in the pathogenesis of Alzheimer's disease. Here, we report all-atom molecular dynamics (MD) simulations to study the interactions of Abeta oligomer with self-assembled monolayers (SAMs) terminated with hydrophobic CH(3) and hydrophilic OH functional groups, with particular interests in how surface chemistry and Abeta orientation affect the adsorption behavior of Abeta. Simulation results show that the CH(3)-SAM has a stronger binding affinity to Abeta than the OH-SAM does, although both surfaces can induce Abeta adsorption. Regardless of the characteristics of the surface, the hydrophobic C-terminal region is more likely to be adsorbed on the SAMs, indicating a preferential orientation and interface for Abeta adsorption. Structural and energetic comparison among six Abeta-SAM systems further reveals that Abeta orientation, SAM surface hydrophobicity, and interfacial waters all determine Abeta adsorption behavior on the surface, highlighting the importance of hydrophobic interactions at the interface. This work may provide parallel insights into the interactions of Abeta with lipid bilayers.

Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective.

Hemagglutinins (HA’s) from duck, swine, and human influenza viruses have previously been shown to prefer avian and human glycan receptor analogues with distinct topological profiles, pentasaccharides LSTa (α-2,3 linkage) and LSTc (α-2,6 linkage), in comparative molecular dynamics studies. On the basis of detailed analyses of the dynamic motions of the receptor binding domains (RBDs) and interaction energy profiles with individual glycan residues, we have identified ∼30 residue positions in the RBD that present distinct profiles with the receptor analogues. Glycan binding constrained the conformational space sampling by the HA. Electrostatic steering appeared to play a key role in glycan binding specificity. The complex dynamic behaviors of the major SSE and trimeric interfaces with or without bound glycans suggested that networks of interactions might account for species specificity in these low affinity and high avidity (multivalent) interactions between different HA and glycans. Contact frequency, energetic decomposition, and H-bond analyses revealed species-specific differences in HA−glycan interaction profiles, not readily discernible from crystal structures alone. Interaction energy profiles indicated that mutation events at the set of residues such as 145, 156, 158, and 222 would favor human or avian receptor analogues, often through interactions with distal asialo-residues. These results correlate well with existing experimental evidence, and suggest new opportunities for simulation-based vaccine and drug development.

A comparative molecular dynamics study on the complexation of alkali metal cations by a poly-ethylene-glycol type podand in water and in dichloromethane

Molecular dynamics (MD) was used to study the complexation of the alkali metal cations (Li +, Na +, K +, Rb + and Cs +) by a poly-ethylene-glycol type podand with eight potential donor oxygen atoms, in water and dichloromethane. MD simulations for the free podand in water provided evidence for a solvent driven stabilizing effect of certain conformations. The complexes in water proved to be unstable as they all dissociated well within the simulation time used. In contrast, the complexes proved to be stable in the organic solvent. Analysis of the MD trajectories for the complexes in dichloromethane showed: (i) an enlargement of the podand OC–CO dihedral angles as the cation size increases; (ii) an increase of the number of strong interactions between the oxygen atoms as the cation size increases; (iii) a considerable degree of solvent penetration into the inner coordination sphere from the potassium to cesium complexes. Quantum calculations showed a higher energetic destabilization for the lithium and sodium complex forms. The results support the experimental evidence that the extraction efficiency shown by this podand (from water to dichloromethane) is higher for potassium, rubidium and cesium than for lithium or sodium.

A comparative molecular dynamics study of diffusion of n-decane and 3-methyl pentane in Y zeolite

Molecular dynamics simulations are reported on the structure and dynamics of n-decane and 3-methylpentane in zeolite NaY. We have calculated several properties such as the center of mass-center of mass rdf, the end-end distance distribution, bond angle distribution and dihedral angle distribution. We have also analysed trajectory to obtain diffusivity and velocity autocorrelation function (VACF). Surprisingly, the diffusivity of 3-methylpentane which is having larger cross-section perpendicular to the long molecular axis is higher than n-decane at 300 K. Activation energies have been obtained from simulations performed at 200 K, 300 K, 350 K, 400 K and 450 K in the NVE ensemble. These results can be understood in terms of the previously known levitation effect. Arrhenious plot has higher value of slope for n-decane (5·9 kJ/mol) than 3-methylpentane (3·7 kJ/mol) in agreement with the prediction of levitation effect.

Molecular dynamics of zervamicin II and its analogs in water and methanol

A comparative study of the molecular dynamics of zervamicin II (an antimicrobial peptide from the peptaibol group, which has the channel-forming activity) in water and methanol has been performed. The influence of amino acid substitutions on the dynamics and stability of the peptide structure has been investigated. The amino acid sequence responsible for the absence of swivel motions in short peptaibols has been determined.

Distinct Glycan Topology for Avian and Human Sialopentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective

Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avian influenza virus infection. It has been previously hypothesized that glycan topology plays a critical role in the human adaptation of avian flu viruses, such as the potentially pandemic H5N1. Comparative molecular dynamics studies are complementary to experimental techniques, including glycan microarray, to understand the mechanism of species-specificity switch better. The examined systems comprise explicitly solvated trimeric forms of avian H3, H5, and swine H9 in complex with avian and human glycan receptor analogues--LSTa (alpha-2,3-linked lactoseries tetrasaccharide a) and LSTc (alpha-2,6-linked lactoseries tetrasaccharide c), respectively. The glycans adopted distinct topological profiles with inducible torsional angles when bound to different HAs. The corresponding receptor binding domain amino acid contact profiles were also distinct. Avian H5 was able to accommodate LSTc in a tightly "folded umbrella"-like topology through interactions with all five sugar residues. After considering conformational entropy, the relative binding free-energy changes, calculated using the molecular mechanics-generalized Born surface area technique, were in agreement with previous experimental findings and provided insights on electrostatic, van der Waals, desolvation, and entropic contributions to HA-glycan interactions. The topology profile and the relative abundance of free glycan receptors may influence receptor binding kinetics. Glycan composition and topological changes upon binding different HAs may be important determinants in species-specificity switch.

Comparative Molecular Dynamics Studies of Wild-Type and Oxidized Forms of Full-Length Alzheimer Amyloid β-Peptides Aβ(1−40) and Aβ(1−42)

In this study, all-atom 50 ns molecular dynamics simulations are performed on the full-length amyloid beta (Abeta) monomers (WT-Abeta(1-40) and WT-Abeta(1-42)) and their oxidized forms (Met35(O)-Abeta(1-40) and Met35(O)-Abeta(1-42)) in aqueous solution. The effects of the oxidation state of Met35 and the presence of dipeptide (Ile41-Ala42) on the secondary structures of the three distinct regions (the central hydrophobic core region 17-21 (LVFFA), the loop 23-28 (DVGSNK), and the second hydrophobic domain 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with the available experimental information. Our simulations indicate that the WT-Abeta(1-40) monomer adopts an overall beta-hairpin-like structure, which is promoted by the turn region (24-27). This turn region is stabilized through salt-bridge formation between the Asp23 and Lys28 residues. In contrast, the overall structure of the oxidized (Met35(O)-Abeta(1-40)) monomer can be divided into three well-defined bend regions separated by coil segments. These structural differences may be critical for the measured decrease in the rate of aggregation of Met35(O)-Abeta(1-40) peptide. In the WT-Abeta(1-42) monomer, in comparison to the WT-Abeta(1-40), the Asp23-Lys28 salt bridge is absent, and consequently, the turn in the middle (24-27) region has a smaller curvature. The observed difference in the aggregation rates of these two peptides may be related to the opening of the turn (24-27) stabilized by the Asp23-Lys28 salt bridge. For WT-Abeta(1-42), in the absence of this salt bridge, the unfolding and aggregation events may be more favorable than for WT-Abeta(1-40).

Comparative study of molecular dynamics, diffusion, and permeability for ligands in biomembranes of different lipid composition

Comparative study of molecular dynamics, diffusion, and permeability for ligands in biomembranes of different lipid composition

A comparative molecular dynamics study on thermostability of human and chicken prion proteins

To compare the thermostabilities of human and chicken normal cellular prion proteins (HuPrPC and CkPrPC), molecular dynamics (MD) simulations were performed for both proteins at an ensemble level (10 parallel simulations at 400K and 5 parallel simulations at 300K as a control). It is found that the thermostability of HuPrPC is comparable with that of CkPrPC, which implicates that the non-occurrence of prion diseases in non-mammals cannot be completely attributed to the thermodynamic properties of non-mammalian PrPC.