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Results for “Molecular Dynamics Simulation”

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PubMed1996

Understanding water: molecular dynamics simulations of myoglobin.

Molecular dynamics simulations were performed on CO myoglobin to evaluate the stability of the bound water molecules as determined in a neutron diffraction analysis. The myoglobin structure derived from the neutron analysis provided the starting coordinate set used in the simulation. The simulations show that only a few water molecules are tightly bound to protein atoms, while most solvent molecules are labile, breaking and reforming hydrogen bonds. Comparison between myoglobin in solution and in a single crystal highlighted some of the packing effects on the solvent structure and shows that water solvent plays an indispensable role in protein dynamics and structural stability. The described observations explain some of the differences in the experimental results of protein hydration as observed in NMR, neutron and X-ray diffraction studies.

Computer Simulation↗

PubMed2007

Cation-pi interactions stabilize the structure of the antimicrobial peptide indolicidin near membranes: molecular dynamics simulations.

We implemented molecular dynamics simulations of the 13-residue antimicrobial peptide indolicidin (ILPWKWPWWPWRR-NH2) in dodecylphosphocholine (DPC) and sodium dodecyl sulfate (SDS) micelles. In DPC, a persistent cation-pi interaction between TRP11 and ARG13 defined the structure of the peptide near the interface. A transient cation-pi interaction was also observed between TRP4 and the choline group on DPC lipids. We also implemented simulation of a mutant of indolicidin in the DPC micelle where TRP11 was replaced by ALA11. As a result of the mutation, the boat-shaped conformation is lost and the structure becomes significantly less defined. On the basis of this evidence, we argue that cation-pi interactions determine the experimentally measured, well-defined boat-shaped structure of indolicidin. In SDS, the lack of such interactions and the electrostatic binding of the terminal arginine residues to the sulfate groups leads to an extended peptide structure. To the best of our knowledge, this is the first time that a cation-pi interaction between peptide side chains has been shown to stabilize the structure of a small antimicrobial peptide. The simulations are in excellent agreement with available experimental measurements: the backbone of the peptide is more ordered in DPC than in SDS; the tryptophan side chains pack against the backbone in DPC and point away from the backbone in SDS; the rms fluctuation of the peptide backbone and peptide side chains is greater in SDS than in DPC; and the peptide backbone order parameters are higher in DPC than in SDS.

Amino Acid Sequence↗

PubMed2005

Cholesterol effects on a mixed-chain phosphatidylcholine bilayer: a molecular dynamics simulation study.

A molecular dynamics simulation of a mono-cis-unsaturated 1-palmitoyl-2-oleoyl-phosphatidylcholine bilayer containing approximately 22 mol% of cholesterol (POPC-Chol) was carried out for 15 ns. An 8-ns trajectory was analysed to determine the effects of Chol on the membrane properties and compare it with that on the fully saturated 1,2-dimyristoyl-phosphatidylcholine bilayer containing approximately 22 mol% of Chol (DMPC-Chol). The study suggests that the experimentally observed weaker effect of Chol on the POPC than DMPC bilayer might result from a different vertical localisation of the Chol hydroxyl group (OH-Chol) in both bilayers: in the POPC-Chol bilayer, OH-Chol is placed approximately 3 A higher in the bilayer interface than in the DMPC-Chol bilayer. Because of the rigid cis double bond in the beta-chain of POPC, Chol fits worse to the POPC-Chol membrane environment and is pushed up, in effect all Chol ring atoms are, on average, located above the double bond. Both in mono-cis-unsaturated and fully saturated PC bilayers, Chol induces stronger van der Waals interactions among the chains, whereas its interactions with the chains are weak. In contrast to DMPC, the smooth alpha-face of the Chol ring lowers the order of POPC chains, whereas the rough beta-face increases the order.

Cholesterol↗

PubMed2000

Transmembrane domains of viral ion channel proteins: a molecular dynamics simulation study.

Nanosecond molecular dynamics simulations in a fully solvated phospholipid bilayer have been performed on single transmembrane alpha-helices from three putative ion channel proteins encoded by viruses: NB (from influenza B), CM2 (from influenza C), and Vpu (from HIV-1). alpha-Helix stability is maintained within a core region of ca. 28 residues for each protein. Helix perturbations are due either to unfavorable interactions of hydrophobic residues with the lipid headgroups or to the need of the termini of short helices to extend into the surrounding interfacial environment in order to form H-bonds. The requirement of both ends of a helix to form favorable interactions with lipid headgroups and/or water may also lead to tilting and/or kinking of a transmembrane alpha-helix. Residues that are generally viewed as poor helix formers in aqueous solution (e.g., Gly, Ile, Val) do not destabilize helices, if located within a helix that spans a lipid bilayer. However, helix/bilayer mismatch such that a helix ends abruptly within the bilayer core destabilizes the end of the helix, especially in the presence of Gly and Ala residues. Hydrogen bonding of polar side-chains with the peptide backbone and with one another occurs when such residues are present within the bilayer core, thus minimizing the energetic cost of burying such side-chains.

Amino Acid Sequence↗

PubMedDate not supplied

Disaccharide conformational flexibility. II. Molecular dynamics simulations of sucrose.

Molecular dynamics simulations have been used to study the motions in vacuum of the disaccharide sucrose. Ensembles of trajectories were calculated for each of the five local minimum energy conformations identified in the adiabatic conformational energy mapping of this molecule. The model sucrose molecules were found to exhibit a variety of motions, although the global minimum energy conformation was found to be dynamically stable, and no transitions away from this structure were observed to occur spontaneously. In all but one of these vacuum trajectories, the intramolecular hydrogen bond between residues was maintained, in accord with recent nmr studies of this molecule in aqueous solution. Considerable flexibility of the furanoid ring was found in the trajectories. No "flips" to the opposite puckering for this ring were found in the simulations starting from the global minimum, although such a transition was observed for a trajectory initiated with one of the higher local minimum energy conformations. Overall, the observed structural fluctuations were consistent with the experimental picture of sucrose as a relatively rigid molecule.

Carbohydrate Conformation↗

PubMed2006

Transient stability of the helical pattern of region F19-L22 of the N-terminal domain of p53: a molecular dynamics simulation study.

Two molecular dynamics simulations of the region E17-N29 of p53 (p53(17-29)) at different temperatures were performed for a total time of 0.2 micros, to study the conformational landscape of this region. Previous studies have suggested that this region displays different structural motifs, such as helix of a double beta-turn, and that its secondary structure might be transiently stable. Interestingly, in this study it was found that the region F19-L25, and particularly its fragment F19-L22, display a stable, transient helical pattern at sub-microsecond periods. The region F19-L22, which contains one of the most important residues needed for the interaction of p53 with MDM2, seems to be formed and stabilized by the existence of one hydrophobic and one aromatic cluster. The main function of these clusters is to help their surrounding area to desolvate, to allow the hydrogen bond network, therefore favoring the formation of a stable helix. This preliminary study would be useful for a better understanding of the structure and function of the N-terminal domain of p53 and its implications for the control of different types of cancer.

Crystallography, X-Ray↗

PubMed1998

Plasticity induced by shock waves in nonequilibrium molecular-dynamics simulations

Nonequilibrium molecular-dynamics simulations of shock waves in three-dimensional 10-million atom face-centered cubic crystals with cross-sectional dimensions of 100 by 100 unit cells show that the system slips along all of the available 111 slip planes, in different places along the nonplanar shock front. Comparison of these simulations with earlier ones on a smaller scale not only eliminates the possibility that the observed slippage is an artifact of transverse periodic boundary conditions, but also reveals the richness of the nanostructure left behind. By introducing a piston face that is no longer perfectly flat, mimicking a line or surface inhomogeneity in the unshocked material, it is shown that for weaker shock waves (below the perfect-crystal yield strength), stacking faults can be nucleated by preexisting extended defects.

Journal Article↗

PubMed2003

Structure formation of supercooled polymers in confined geometries--a molecular-dynamics simulation study.

Molecular-dynamics simulations of thin polymer films are performed with a recently introduced coarse-grained model. This model reproduces many features of polymer crystallization from the melt. In this work, we show how confining walls influence the structure formation depending on the degree of supercooling. Already in the melt at high temperature a preorder is induced near the walls. On lowering the temperature, crystalline order nucleates at the walls, from which it propagates into the film. We show how this growth can be influenced by prestructuring the wall.

Journal Article↗

PubMed1985

Atomic motions in phenylalanine transfer RNA probed by molecular dynamics simulations.

A 24 psec molecular dynamics simulation of tRNAPhe reveals a very stable model whose average structure is close to that of the crystallographic studies. The root mean square atomic motions correlate very well with the thermal factors from crystallography and are largely determined by packing forces. These motions are generally more anisotropic than those seen in a molecular dynamics simulation of a globular protein, and the anisotropic effects are also primarily a consequence of packing considerations. The development and examination of molecular dynamics models for macromolecules is an interesting basic research problem in biophysical chemistry, and it is now reasonably well advanced. The more exciting tasks of using these models to predict experimental properties and to examine biological function are just beginning.

Models, Molecular↗

PubMed2003

Hydrogen bonding interactions between aldose reductase complexed with NADP(H) and inhibitor tolrestat studied by molecular dynamics simulations and binding assay.

Molecular dynamics simulations and binding affinity studies have been carried out in order to probe the effect of the charge state of His110 and cofactor NADPH on the binding affinity of the potent inhibitor tolrestat to aldose reductase (ALR2) complexed with either NADPH or NADP(+). Molecular dynamics simulations of ALR2-NADP(+)-tolrestat indicate that the carboxylate group of tolrestat forms a hydrogen bond with Tyr48 and His110 of ALR2 regardless of the charge state of His110. In the case of ALR2-NADPH-tolrestat, the H-bonding pattern is significantly different from that of ALR2-NADP(+)-tolrestat, in that Tyr48 does not H-bond to tolrestat. The binding affinity of tolrestat to ALR2 complexed with either NADPH or NADP(+) is comparable and pH-dependent. Based on the H-bonding interactions seen in computer simulations, it is proposed that the cationic moiety at the active site of ALR2-NADP(+) and ALR2-NADPH that interacts with the carboxylate of tolrestat is NADP(+) and His110, respectively. The residue that gives rise to the pH-dependent binding of tolrestat to ALR2-NADP(+) and ALR2-NADPH has been identified as Tyr48 and His110, respectively.

Aldehyde Reductase↗

PubMed2005

Effect of PNA backbone modifications on cyanine dye binding to PNA-DNA duplexes investigated by optical spectroscopy and molecular dynamics simulations.

Optical spectroscopy and molecular dynamics simulations have been used to study the interaction between a cationic cyanine dye and peptide nucleic acid (PNA)-DNA duplexes. This recognition event is important because it leads to a visible color change, signaling successful hybridization of PNA with a complementary DNA strand. We previously proposed that the dye recognized the minor groove of the duplex, using it as a template for the assembly of a helical aggregate. Consistent with this, we now report that addition of isobutyl groups to the PNA backbone hinders aggregation of the dye when the substituents project into the minor groove but have a weaker effect if directed out of the groove. UV-Visible and circular dichroic spectroscopy were used to compare aggregation on the different PNA-DNA duplexes, while molecular dynamics simulations were used to confirm that the substituents block the minor groove to varying degrees, depending on the configuration of the starting amino acid. In addition to a simple steric blockage effect of the substituent, the simulations suggest that directing the isobutyl group into the minor groove causes the groove to narrow and the duplex to become more rigid, structural perturbations that are relevant to the growing interest in backbone-modified PNA for applications in the biological and materials sciences.

Benzothiazoles↗

PubMed2006

Structures and properties of Newton black films characterized using molecular dynamics simulations.

We used molecular dynamics (MD) simulations to investigate the structures and properties of Newton black films (NBF) for several surfactants: sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (C16TAB), and surfactin using film thicknesses up to 10 nm. By calculating the interface formation energy for various packing conditions on the surface pressure-area isotherm, we found that the most probable surface concentration is approximately 42 A(2)/molecule for SDS and C16TAB and approximately 170 A(2)/molecule for surfactin. We then used this most probable concentration of each surfactant to simulate NBF with various film thicknesses. From analyzing the disjoining pressure-film thickness isotherms with the density profiles and the solvation coordination number, we found that the increase of the disjoining pressure during the film thinning was coupled with the change in inner structure of the NBF (i.e., density profile and the solvation of ionic entities). In the range of film thicknesses less than approximately 30 A, the disjoining pressures for the SDS and C16TAB were found to be larger than that of the surfactin. We predicted the Gibbs elasticity (175 dyn/cm for surfactin; 109 dyn/cm for C16TAB; 38 dyn/cm for SDS) required to assess the stability of NBF against surface concentration fluctuations, and the shear modulus (6.5 GPa for the surfactin; 6.1 GPa for the C16TAB; 3.5 GPa for the SDS) and the yield stress (approximately 0.8 GPa for surfactin; approximately 0.8 GPa for C16TAB; approximately 0.4 GPa for the SDS) to assess the mechanical stability against the externally imposed mechanical perturbation.

Algorithms↗

PubMed1994

Investigation of shape variations in the antibody binding site by molecular dynamics computer simulation.

Molecular dynamics simulations have been used to investigate the flexibility and variations in the shape of the binding site of an antibody against human Rhinovirus serotype 2 (HRV2) and its complex with a 15 amino acid oligopeptide, the structure of which has been recently determined by X-ray crystallography. During the simulation of the unbound antibody the binding site, defined in terms of the hypervariable regions or complementarity determining regions (CDRs), shows significant fluctuations in shape. For the complex such variations in the shape of the binding site were reduced. The largest fluctuations in the unbound antibody occurred within the CDR-H3. The largest differences between the bound and unbound crystal structures are also associated with CDR-H3. The relative displacements of the loops have been analysed in terms of internal distortions, rigid body motions of the loops and changes with respect to the framework regions. The degree to which the motions of the loops are correlated and the variation in the volume of the binding pocket during the simulation have also been examined.

Amino Acid Sequence↗

PubMed2006

Evidence in support of levitation effect as the reason for size dependence of ionic conductivity in water: a molecular dynamics simulation.

We report extensive molecular dynamics simulations of (i) model ions in water at high concentrations as a function of the size and charge of the ion as well as (ii) realistic simulation of Cl- and Br- ions at low concentrations in water at room temperature. We also analyze existing experimental data in light of the results obtained here. The halide ion simulations have been carried out using the interaction potentials of Koneshan et al. (J. Phys. Chem. B 1998, 102, 4193). We compute structural and dynamical properties of ions in water and explore their variation with size and charge of the ion. We find that ions of certain intermediate sizes exhibit a maximum in self-diffusivity in agreement with previous experimental measurements and computer simulations. We analyze molecular dynamics trajectories in light of the previous understanding of the levitation effect (LE) and the recent suggestion that ionic conductivity has its origin in LE (J. Phys. Chem. B 2005, 109, 8120). We report the distribution of void and neck radii that exist amidst water. Our analysis suggests that the ion with maximum self-diffusivity is characterized by a lower activation energy and a single-exponential decay of F(s)(k,t). The behavior of these and other related quantities of the ion with maximum self-diffusivity are characteristic of the anomalous regime of the LE. The simulation results of Br- and Cl- ions in water also yield results in agreement with the predictions of LE. A plot of experimental conductivity data in the literature for alkali ions in water by Kay and Evans (J. Phys. Chem. 1966, 70, 2325) also yields a lower activation energy for the ion with maximum conductivity in excellent agreement with the LE. To the best of our knowledge, none of the existing theories predict a lower activation energy for the ion with maximum conductivity.

Journal Article↗

PubMed1990

Molecular dynamics simulations in biology.

Molecular dynamics--the science of simulating the motions of a system of particles--applied to biological macromolecules gives the fluctuations in the relative positions of the atoms in a protein or in DNA as a function of time. Knowledge of these motions provides insights into biological phenomena such as the role of flexibility in ligand binding and the rapid solvation of the electron transfer state in photosynthesis. Molecular dynamics is also being used to determine protein structures from NMR, to refine protein X-ray crystal structures faster from poorer starting models, and to calculate the free energy changes resulting from mutations in proteins.

Chemical Phenomena↗

PubMed2005

Understanding human 15-hydroxyprostaglandin dehydrogenase binding with NAD+ and PGE2 by homology modeling, docking and molecular dynamics simulation.

Homology modeling, molecular docking, and molecular dynamics simulation have been performed to determine human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) binding with its NAD+ cofactor and prostaglandin E2 (PGE2) substrate. The computational studies have led to a three-dimensional (3D) model of the entire 15-PGDH-NAD+-PGE2 complex, demonstrating the detailed binding of PGE2 with 15-PGDH for the first time. This 3D model shows specific interactions of the protein with the cofactor and substrate in qualitative agreement with available experimental data. Our model demonstrates the PGE2-binding cavity of the protein for the first time. The model further leads to an interesting prediction that the catalytic activity of 15-PGDH should also significantly be affected by Gln148, in addition to the previously known three catalytic residues (Ser138, Tyr151, and Lys155). The reported 3D model of 15-PGDH-NAD+-PGE2 complex might be valuable for future rational design of novel inhibitors of 15-PGDH.

Amino Acid Sequence↗

PubMed1998

Ab initio modeling and molecular dynamics simulation of the alpha 1b-adrenergic receptor activation.

This work describes the ab initio procedure employed to build an activation model for the alpha 1b-adrenergic receptor (alpha 1b-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the employment of experimental validations of the model in each upgrading step. A combined simulated (molecular dynamics) and experimental mutagenesis approach was used to determine the structural and dynamic features characterizing the inactive and active states of alpha 1b-AR. The latest version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha 1b-AR activation in terms of molecular structure and dynamics allows further complications of the model to allow prediction and interpretation of an ever-increasing number of experimental data.

Amino Acid Sequence↗

PubMed2006

Calculation of the entropy and free energy of peptides by molecular dynamics simulations using the hypothetical scanning molecular dynamics method.

Hypothetical scanning (HS) is a method for calculating the absolute entropy S and free energy F from a sample generated by any simulation technique. With this approach each sample configuration is reconstructed with the help of transition probabilities (TPs) and their product leads to the configuration's probability, hence to the entropy. Recently a new way for calculating the TPs by Monte Carlo (MC) simulations has been suggested, where all system interactions are taken into account. Therefore, this method--called HSMC--is in principle exact where the only approximation is due to insufficient sampling. HSMC has been applied very successfully to liquid argon, TIP3P water, self-avoiding walks on a lattice, and peptides. Because molecular dynamics (MD) is considered to be significantly more efficient than MC for a compact polymer chain, in this paper HSMC is extended to MD simulations as applied to peptides. Like before, we study decaglycine in vacuum but for the first time also a peptide with side chains, (Val)(2)(Gly)(6)(Val)(2). The transition from MC to MD requires implementing essential changes in the reconstruction process of HSMD. Results are calculated for three microstates, helix, extended, and hairpin. HSMD leads to very stable differences in entropy TDeltaS between these microstates with small errors of 0.1-0.2 kcal/mol (T=100 K) for a wide range of calculation parameters with extremely high efficiency. Various aspects of HSMD and plans for future work are discussed.

Chemistry, Physical↗