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PubMed1993

Improved molecular dynamics simulations for the determination of peptide structures.

In this article a few methods or modifications proven to be useful in the conformational examination of peptides and related molecules by molecular dynamics are illustrated. The first is the explicit use of organic solvents in the simulations. For many cases such solvents are appropriate since the nmr measurements (or other experimental observations) were carried out in the same solvent. Here, the use of dimethylsulfoxide and chloroform in molecular dynamics is described, with some advantages of the use of these solvents high-lighted. A constant allowing for the scaling of the nonbonded interactions of the force field, an idea previously employed in distance geometry and simulated annealing, has been implemented. The usefulness of this method is that when the nonbonded term is turned to zero, atoms can pass through each other, while the connectivity of the molecule is maintained. It will be shown that such simulations, if a sufficient driving force is present (i.e., nuclear Overhauser effects restraints), can produce the correct stereoconfiguration (i.e., chiral center) as well as configurational isomer (i.e., cis/trans isomers). Lastly, a penalty term for coupling constants directly related to the Karplus curve has been implemented into the potential energy force field. The advantages of this method over the commonly used dihedral angle restraining are discussed. In particular, it is shown that with more than one coupling constant about a dihedral angle a great reduction of the allowed conformational space is obtained.

Algorithms↗
PubMed2006

Full length Vpu from HIV-1: combining molecular dynamics simulations with NMR spectroscopy.

Based on structures made available by solution NMR, molecular models of the protein Vpu from HIV-1 were built and refined by 6 ns MD simulations in a fully hydrated lipid bilayer. Vpu is an 81 amino acid type I integral membrane protein encoded by the human immunodeficiency virus type-1 (HIV-1) and closely related simian immunodeficiency viruses (SIVs). Its role is to amplify viral release. Upon phosphorylation, the cytoplasmic domain adopts a more compact shape with helices 2 and 3 becoming almost parallel to each other. A loss of helicity for several residues belonging to the helices adjacent to both ends of the loop region containing serines 53 and 57 is observed. A fourth helix, present in one of the NMR-based structures of the cytoplasmic domain and located near the C-terminus, is lost upon phosphorylation.

Amino Acid Sequence↗
PubMed1987

A molecular dynamics simulation of crystalline alpha-cyclodextrin hexahydrate.

The structure of crystalline alpha-cyclodextrin (alpha-CD) hexahydrate, form I (C36H60O30.6H2O, space group P2(1)2(1)2(1)) is experimentally so well determined by X-ray and by neutron diffraction analyses that the positions of all the hydrogen atoms are available. This provides an opportunity for testing an empirical force field that is currently used in simulations of protein and nucleic acid structures by performing molecular dynamics studies employing the GROMOS program package on a system of 4 unit cells containing 16 alpha-CD molecules and 96 water molecules. A detailed comparison of the simulated and experimentally determined crystal structures shows that the experimental positions of the alpha-CD atoms are reproduced within 0.025 nm, well within the overall experimental accuracy of 0.036 nm; that the water molecules are on average within 0.072 nm from their experimental sites, with two thirds reproduced within experimental accuracy by the calculations; that high correlation is produced between the occurrence of simulated and experimentally observed hydrogen bonds. The good agreement between simulated and experimental results suggests that the tested force field is reliable.

Carbohydrate Conformation↗
PubMed2002

Molecular dynamics simulations of glycoclusters and glycodendrimers.

Protein-carbohydrate recognition plays a crucial role in a wide range of biological processes, required both for normal physiological functions and the onset of disease. Nature uses multivalency in carbohydrate-protein interactions as a strategy to overcome the low affinity found for singular binding of an individual saccharide epitope to a single carbohydrate recognition domain of a lectin. To mimic the complex multi-branched oligosaccharides found in glycoconjugates, which form the structural basis of multivalent carbohydrate-protein interactions, so-called glycoclusters and glycodendrimers have been designed to serve as high-affinity ligands of the respective receptor proteins. To allow a rational design of glycodendrimer-type molecules with regard to the receptor structures involved in carbohydrate recognition, a deeper knowledge of the dynamics of such molecules is desirable. Most glycodendrimers have to be considered highly flexible molecules with their conformational preferences most difficult to elucidate by experimental methods. Longtime molecular dynamics (MD) simulations with inclusion of explicit solvent molecules are suited to explore the conformational space accessible to glycodendrimers. Here, a detailed geometric and conformational analysis of 15 glycodendrimers and glycoclusters has been accomplished, which differ with regard to their core moieties, spacer characteristics and the type of terminal carbohydrate units. It is shown that the accessible conformational space depends strongly on the structural features of the core and spacer moieties and even on the type of terminating sugars. The obtained knowledge about possible spatial distributions of the sugar epitopes exposed on the investigated hyperbranched neoglycoconjugates is detailed for all examples and forms important information for the interpretation and prediction of affinity data, which can be deduced from biological testing of these multivalent neoglycoconjugates.

Carbohydrate Conformation↗
PubMed2002

Compression of carbon nanotubes filled with C60, CH4, or Ne: predictions from molecular dynamics simulations.

The effect of filling nanotubes with C60, CH4, or Ne on the mechanical properties of the nanotubes is examined. The approach is classical molecular dynamics using the reactive empirical bond order (REBO) and the adaptive intermolecular REBO potentials. The simulations predict that the buckling force of filled nanotubes can be larger than that of empty nanotubes, and the magnitude of the increase depends on the density of the filling material. In addition, these simulations demonstrate that the buckling force of empty nanotubes depends on temperature. Filling the nanotube disrupts this temperature effect so that it is no longer present in some cases.

Journal Article↗
PubMed1998

Studies on the conformational behaviour of GlcNAc-Man3-GlcNAc2 oligosaccharides using molecular dynamics simulations.

Three-dimensional structures of the natural substrate unit for the enzyme N-acetylglucosamine-transferase II, GIcNAc-Man3-GlcNAc2, were investigated by molecular modelling methods. Molecular dynamics (MD) and molecular mechanics calculations on two hexasaccharides, namely GlcNAc-Man3-GlcNAc2-Asn and GlcNAc-Man3-GlcNAc2-OMe were performed by the Biosym/MSI software using the CVFF and CFF95 force fields in vacuum. The MD simulations were calculated for 3 ns at different simulation temperatures and for two values of dielectric constant, epsilon=1 and epsilon=4. From each 3 ns trajectory, 3050 structures have been optimized. The local minima obtained have been clustered into families exhibiting similar values of glycosidic torsional angles phi, psi, and omega. The influence of the simulation conditions and force fields used on the conformational behaviour and structure of the title oligosaccharides is discussed.

Acetylglucosamine↗
PubMed2005

Layered interfaces between immiscible liquids studied by density-functional theory and molecular-dynamics simulations.

We present a study of the structure in the interface between two immiscible liquids by density-functional theory and molecular-dynamics calculations. The liquids are modeled by Lennard-Jones potentials, which achieve immiscibility by suppressing the attractive interaction between unlike particles. The density profiles of the liquids display oscillations only in a limited part of the simple liquid-phase diagram (rho,T). When approaching the liquid-vapor coexistence, a significant depletion appears while the layering behavior of the density profile vanishes. By analogy with the liquid-vapor interface and the analysis of the adsorption this behavior is suggested to be strongly related to the drying transition.

Adsorption↗
PubMed1994

Dynamic simulation of molecular and ionic materials.

Two new programs perform molecular dynamics simulations on molecular and ionic materials, respectively. The first simulates systems of small molecules, treated dynamically as rigid bodies, with interactions of the site-site Lennard-Jones form, plus point charges. The second simulates systems of point ions, which may be made polarizable by means of the shell model, treated by the method of adiabatic dynamics. Both programs handle Coulombic interactions in periodic boundaries by means of the Ewald sum. Force evaluations make use of efficient neighbor-search algorithms. The programs incorporate extensive analysis options in terms of structural and dynamic correlation functions. The programs are controlled by a command language, Dynamo, which provides a good environment for further development, as well as ease of use and flexibility in the choice of simulation protocol.

Algorithms↗
PubMed2004

Anomalous mixing behavior of polyisobutylene/polypropylene blends: molecular dynamics simulation study.

The unusual mixing behavior of polyisobutylene (PIB) with head-to-head (hhPP) and head-to-tail polypropylene (PP) is studied using large-scale molecular dynamics (MD). The heats of mixing and Flory chi parameters were computed from MD simulations of both blends using a united atom model. The chi parameters from the simulations were estimated from the structure factors using the random phase approximation in analogy with neutron scattering (SANS) experiments. MD simulations for syndiotactic hhPP/PIB predicted a lower critical solution temperature with a chi parameter in very good agreement with SANS experiments on the atactic hhPP/PIB blend. MD simulations also predicted that the isotactic PP/PIB blend was immiscible at high molecular weight in qualitative agreement with cloud point measurements on atactic PP/PIB.

Journal Article↗
PubMed2005

Classical molecular-dynamics simulation of the hydroxyl radical in water.

We have studied the hydration and diffusion of the hydroxyl radical OH0 in water using classical molecular dynamics. We report the atomic radial distribution functions, hydrogen-bond distributions, angular distribution functions, and lifetimes of the hydration structures. The most frequent hydration structure in the OH0 has one water molecule bound to the OH0 oxygen (57% of the time), and one water molecule bound to the OH0 hydrogen (88% of the time). In the hydrogen bonds between the OH0 and the water that surrounds it the OH0 acts mainly as proton donor. These hydrogen bonds take place in a low percentage, indicating little adaptability of the molecule to the structure of the solvent. All hydration structures of the OH0 have shorter lifetimes than those corresponding to the hydration structures of the water molecule. The value of the diffusion coefficient of the OH0 obtained from the simulation was 7.1x10(-9) m2 s(-1), which is higher than those of the water and the OH-.

Algorithms↗
PubMed1998

Conformational sampling of CDR-H3 in antibodies by multicanonical molecular dynamics simulation.

The diversity in the lengths and the amino acid sequences of the third complementarity determining region of the antibody heavy chain (CDR-H3) has made it difficult to establish a relationship between the sequences and the tertiary structures, in contrast to the other CDRs, which are classified by their canonical structures. Enhanced conformational sampling of two different CDR-H3s was performed by multicanonical molecular dynamics (multicanonical MD) simulation while restricting the base structures, with and without the other surrounding CDR segments. The results showed that the multicanonical MD sampled a much larger conformational space than the conventional MD, independent of the initial conformations of the simulations. When the other CDRs surrounding the CDR-H3 segments were included in the calculations, the predominant conformations at 300 K corresponded to the X-ray crystal structures. When only the single CDR-H3 loops were considered with the restricted base structures, a greater number of different conformations were sampled as putative loops, but only a small number of stable conformations appeared at 300 K. Analyses of the resultant conformations revealed a structural role for the glycine, when it is located at position three residues before the last residue of CDR-H3 (Gly-X-X-last residue), coincident with the statistical tendencies of many antibody crystal structures. This reflects the general consistency between the energetically stable conformations and the empirically observed conformations. The current method is expected to be applicable to the structural modeling and the design of antibodies, especially for the inherently flexible loops.

Algorithms↗
PubMed2005

Prediction of molecular-dynamics simulation results using feedforward neural networks: reaction of a C2 dimer with an activated diamond (100) surface.

A new approach involving neural networks combined with molecular dynamics has been used for the determination of reaction probabilities as a function of various input parameters for the reactions associated with the chemical-vapor deposition of carbon dimers on a diamond (100) surface. The data generated by the simulations have been used to train and test neural networks. The probabilities of chemisorption, scattering, and desorption as a function of input parameters, such as rotational energy, translational energy, and direction of the incident velocity vector of the carbon dimer, have been considered. The very good agreement obtained between the predictions of neural networks and those provided by molecular dynamics and the fact that, after training the network, the determination of the interpolated probabilities as a function of various input parameters involves only the evaluation of simple analytical expressions rather than computationally intensive algorithms show that neural networks are extremely powerful tools for interpolating the probabilities and rates of chemical reactions. We also find that a neural network fits the underlying trends in the data rather than the statistical variations present in the molecular-dynamics results. Consequently, neural networks can also provide a computationally convenient means of averaging the statistical variations inherent in molecular-dynamics calculations. In the present case the application of this method is found to reduce the statistical uncertainty in the molecular-dynamics results by about a factor of 3.5.

Journal Article↗
PubMed2005

Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods.

Taking advantage of the Trp73 residue located close to the 4E-BP binding site of eIF4E, the interaction between the 4E-BP isoform and eIF4E was investigated by the Trp fluorescence titration method. Although no significant difference was observed among the association constants of three 4E-BP isoforms, the binding preference of 4E-BP2 over 4E-BP1 and -BP3 was shown, probably due to the effect of a 4E-BP2-specific LDRR (60-63) sequence for the binding with eIF4E. By contrast, surface plasmon resonance (SPR) analyses showed the binding preference of 4E-BP1, although the difference among the isoforms was also not significant. This inconsistency with fluorescence analysis likely resulted from the different observation points of the interaction, i.e., local and overall interactions observed by the fluorescence and SPR methods, respectively. To clarify the structural basis for these spectroscopic results, the crystal structure of the ternary complex of m7GpppA-eIF4E-4E-BP1 fragment (Thr36-Thr70) was analyzed by the X-ray diffraction method. Crystal structure analysis at 2.1 A resolution revealed that the 4E-BP1 fragment, assigned to the Pro47-Pro66 peptide moiety, adopted a reverse L-shaped conformation involving the beta sheet and alpha-helical structures and was located at the root of the handle of the temple-bell-shaped eIF4E through hydrophilic and hydrophobic interactions. Based on the observed binding mode, possible interactions with the three 4E-BP isoforms have been discussed. On the other hand, since the crystal structural comparison with the previously determined m7GpppA-eIF4E-4E binary complex showed that the docking of the 4E-BP1 fragment does not significantly affect the overall tertiary structure and cap-binding scaffold of eIF4E, the dynamic regulation of the cap-binding of eIF4E by 4E-BP1 was investigated by molecular dynamics (MD) simulations. Consequently, the simulation suggested that (i) the helical region of the 4E-BP1 peptide is important for the binding with eIF4E, (ii) the existence of a cap structure stabilizes the binding of eIF4E with 4E-BP, (iii) the binding of 4E-BP stabilizes the cap-binding pocket of eIF4E, and (iv) the phosphorylation of Ser67 alone does not induce the separation of 4E-BP from eIF4E, but increases the structural rigidity of 4E-BP. These results provide the structural basis for the mRNA cap-binding regulation of eIF4E by 4E-BP.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Molecular dynamics simulations of Trp side-chain conformational flexibility in the gramicidin A channel.

Gramicidin A (gA) is prototypical peptide antibiotic and a model ion channel former. Configured in the solid-state NMR beta(6.5)-helix channel conformation, gA was subjected to 1-ns molecular dynamics (MD) gas phase simulations using the all-atom charmm22 force field to ascertain the conformational stability of the Trp side chains as governed by backbone and neighboring side-chain contacts. Three microcanonical trajectories were computed using different initial atomic velocities for each of twenty different initial structures. For each set, one of the four Trp side chains in each monomer was initially positioned in one of the five non-native conformations (A. E. Dorigo et al., Biophysical Journal, 1999, Vol. 76, 1897-1908), the other Trps being positioned in the native state, o1. In three additional control simulations, all Trps were initiated in the native conformation. After equilibration, constraints were removed and subsequent conformational changes of the initially constrained Trp were measured. The chi(1) was more flexible than chi(2.1). The energetically optimal orientation, o1 (Dorigo et al., 1999), was the most stable in all four Trp positions (9, 11, 13, 15) and remained unchanged for the entire 1 ns simulation in 19 of 24 trials. Changes in chi(1) from each of the 5 suboptimal states occur readily. Two of the non-native conformations reverted readily to o1, whereas the other three converted to an intermediate state, i2. There were frequent interconversions between i2 and o1. We speculate that experimentally observed Trp stability is caused by interactions with the lipid-water interface, and that stabilization of one of the suboptimal conformations in gA, such as i2, by lipid headgroups could produce a secondary, metastable conformational state. This could explain recent experimental studies of differences in the channel conductance dispersity between gA and a Trp-to-Phe gA analog, gramicidin M (gM, J. C. Markham et al., Biochimica et Biophysica Acta, 2001, Vol. 1513, 185-192).

Dimerization↗
PubMed2006

Molecular dynamics simulations of the melting of 1,3,3-trinitroazetidine.

Physical properties of condensed-phase 1,3,3-trinitroazetidine (TNAZ) have been computed with molecular dynamics (MD) and a nonreactive, fully flexible force field formulated by combining the intramolecular interactions obtained from the Generalized AMBER Force Field and the rigid-molecule force field developed by Sorescu-Rice-Thompson [J. Phys. Chem. B 1997, 101, 798] (AMBER-SRT). The results are compared with MD calculations, using the AMBER force field. The predicted densities of crystalline TNAZ from both force fields are about 10% lower than the experimental value. The calculated thermodynamic melting point at 1 atm from the AMBER-SRT force field is 390 K, in good agreement with the measured value of 374 K, while the AMBER force field predicts a thermodynamic melting point of 462 K. The lattice parameters and the molecular and crystal structures calculated with the AMBER-SRT force field are in excellent agreement with experiment. Simulations with the AMBER-SRT force field were also used to generate the isotherm of TNAZ up to 4 GPa and the bulk modulus and its pressure derivative.

Journal Article↗
PubMed2002

Ions and counterions in a biological channel: a molecular dynamics simulation of OmpF porin from Escherichia coli in an explicit membrane with 1 M KCl aqueous salt solution.

A 5 ns all-atom molecular dynamics trajectory of Escherichia coli OmpF porin embedded in an explicit dimyristoyl-phosphatidylcholine (DMPC) bilayer bathed by a 1 M [KCl] aqueous salt solution is generated to explore the microscopic details of the mechanism of ion permeation. The atomic model includes the OmpF trimer, 124 DMPC, 13470 water molecules as well as 231 K+ and 201 Cl-, for a total of 70,693 atoms. The structural and dynamical results are in excellent agreement with the X-ray data. The global root-mean-square deviation of the backbone atoms relative to the X-ray structure is 1.4 A. A cluster of three fully charged arginine (Arg42, Arg82, and Arg132) facing two acidic residues (Asp113 and Glu117) on L3 in the narrowest part of the aqueous pore is observed to be very stable in the crystallographic conformation. In this region of the pore, the water molecules are markedly oriented perpendicular to the channel axis due to the strong transversal electrostatic field arising from those residues. On average the size of the pore is smaller during the simulation than in the X-ray structure, undergoing small fluctuations. No large movements of loop L3 leading to a gating of the pore are observed. Remarkably, it is observed that K+ and Cl- follow two well-separated average pathways spanning over nearly 40 A along the axis of the pore. In the center of the monomer, the two screw-like pathways have a left-handed twist, undergoing a counter-clockwise rotation of 180 degrees from the extracellular vestibule to the pore periplasmic side. In the pore, the dynamical diffusion constants of the ions are reduced by about 50% relative to their value in bulk solvent. Analysis of ion solvation across the channel reveals that the contributions from the water and the protein are complementary, keeping the total solvation number of both ions nearly constant. Unsurprisingly, K+ have a higher propensity to occupy the aqueous pore than Cl-, consistent with the cation selectivity of the channel. However, further analysis suggests that ion-ion pairs play an important role. In particular, it is observed that the passage of Cl- occurs only in the presence of K+ counterions, and isolated K+ can move through the channel and permeate on their own. The presence of K+ in the pore screens the negative electrostatic potential arising from OmpF to help the translocation of Cl- by formation of ion pairs.

Computer Simulation↗
PubMed2004

Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis.

AIM: Based on the structural analysis to reveal the mechanism of ligand binding to beta-secretase and the specificity of each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free beta-secretase and ligand bound beta-secretase. The trajectories were analyzed using the essential dynamics, and the significant conformational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDom analyses clearly showed that the beta-secretase experienced a large conformational change upon the substrate or inhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate the ligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysis revealed that residues at P2, P1, and P1' positions of the inhibitor were very important for the binding, and residues at P2' and P3' positions may be modified to improve the binding specificity. S3 subsite of the enzyme still had space to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented here is valuable and could be used to identify small molecular inhibitors of beta-secretase.

Amyloid Precursor Protein Secretases↗
PubMed2006

A molecular dynamics simulation of SNase and its hydration shell at high temperature and high pressure.

Temperature- and pressure-induced unfolding of staphylococcal nuclease (SNase) was studied by Royer, Winter et al. using a variety of experimental techniques (SAXS, FT-IR and fluorescence spectroscopy, DSC, PPC, densimetry). For a more detailed understanding of the underlying mechanistic processes of the different unfolding scenarios, we have carried out a series of molecular dynamics (MD) computer simulations on SNase. We investigated the initial changes of the structure of the protein upon application of pressure (up to 5 kbar) and discuss volumetric and structural differences between the native and pressure pre-denatured state. Additionally, we have obtained the compressibility of the protein and hydration water and compare these data with experimental results. As water plays a crucial role in determining the structure, dynamics and function of proteins, we undertook a detailed analysis of the structure of the interfacial water and the protein-solvent H-bond network as well. Moreover, we report here also MD results on the temperature-induced unfolding of SNase. The time evolution of the protein volume and solvent accessible surface area during thermal unfolding have been investigated, and we present a detailed discussion of the temperature-induced unfolding pathway of SNase in terms of secondary and tertiary structural changes.

Computer Simulation↗