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At least 325 records · Page 18Linked to original sources
PubMed2006

The improvement of the algorithm for order parameter calculation (S2) from molecular dynamics simulation using the correlation motion function.

The generalized order parameter, S2, calculated from MD simulation trajectory using time-dependent internal Correlation Motion Function (CMF) agrees well with NMR derived S2 processed with the extended model-free analysis approach. However, the former lies considerably lower comparing to simple model-free derived data from NMR experiments. In the present study we analyze possible reasons of such disagreement. In the general case we propose to use preexponential factors from expression for internal CMF rather than ordinary S2 values. Particularly, in case of the simple model-free S(2) experimental values we suggest comparing them with S2(eff)=1+S2-Sf2 computed from MD simulation data. We show that the S2(eff) values are in a good agreement with NMR derived S2 values obtained using the simple model-free analysis.

Algorithms↗
PubMed2005

IR spectra of N-methylacetamide in water predicted by combined quantum mechanical/molecular mechanical molecular dynamics simulations.

We applied the combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulation method in assessing IR spectra of N-methylacetamide and its deuterated form in aqueous solutions. The model peptide is treated at the Austin Model 1 (AM1) level and the induced dipole effects by the solvent are incorporated in fluctuating solute dipole moments, which are calculated using partial charges from Mulliken population analyses without resorting to any available high-level ab initio dipole moment data. Fourier transform of the solute dipole autocorrelation function produces in silico IR spectra, in which the relative peak intensities and bandwidths of major amide bands are quantitatively compatible with experimental results only when both geometric and electronic polarizations of the peptide by the solvent are dealt with at the same quantum-mechanical level. We cast light on the importance of addressing dynamic charge fluctuations of the solute in calculating IR spectra by comparing classical and QM/MM MD simulation results. We propose the adjustable scaling factors for each amide mode to be directly compared with experimental data.

Acetamides↗
PubMed2000

Conformational properties of a cyclic peptide bradykinin B2 receptor antagonist using experimental and theoretical methods.

The solution conformation of the cyclic peptide J324 (cyclo0,6-[Lys0,Glu6,D-Phe7]BK), an antagonist targeted at the bradykinin (BK) B2 receptor, has been investigated using experimental and theoretical methods. In order to gain insight into the structural requirements essential for BK antagonism, we carried out molecular dynamics (MD) simulations using simulated annealing as the sampling protocol. Following a free MD simulation we performed simulations using nuclear Overhauser enhancement (NOE) distance constraints determined by NMR experiments. The low-energy structures obtained were compared with each other, grouped into families and analyzed with respect to the presence of secondary structural elements in their backbone. We also introduced new ways of plotting structural data for a more comprehensive analysis of large conformational sets. Finally, the relationship between characteristic backbone conformations and the spatial arrangement of specific pharmacophore centers was investigated.

Bradykinin Receptor Antagonists↗
PubMed2005

Tyrosinase inhibition: conformational analysis based studies on molecular dynamics calculations of bipiperidine based inhibitors.

Two series of variably N-substituted biperidines were synthesized by condensing various acid chlorides, alkyl halides and anhydrides with 1,4-bipiperidine. The new compounds were tested as tyrosinase inhibitors and a structure-activity relationship (SAR) study was carried out. Potent inhibition was observed in the case of the 4'-methylbenzyl substitution on this atom (IC50 = 1.72 microM) with this compound being a lead for future drug design. Additionally, calculations of the important QSAR molecular descriptors were done on the biperidine analogues after their 2 ps molecular dynamics (MD) simulations using molecular mechanics force field (MMFF) approaches. Using MD simulations potential and total energies were calculated for the energy minimized models of bipiperidine and the most active analogs 2, 3, 4, 6, 8 and 10.

Enzyme Inhibitors↗
PubMed2006

Effects of temperature and salt concentration on the structural stability of human lymphotactin: insights from molecular simulations.

Extensive molecular dynamics (MD) simulations ( approximately 70 ns total) with explicit solvent molecules and salt ions are carried out to probe the effects of temperature and salt concentration on the structural stability of the human Lymphotactin (hLtn). The distribution of ions near the protein surface and the stability of various structural motifs are observed to exhibit interesting dependence on the local sequence and structure. Whereas chloride association to the protein is overall enhanced as the temperature increases, the sodium distribution in the C-terminal helical region and, to a smaller degree, the chloride distribution in the same region are found higher at the lower temperature. The similar trend is also observed in nonlinear Poisson-Boltzmann calculations with a temperature-dependent water dielectric constant, once conformational averaging over a series of MD snapshots is done. The unexpected temperature dependence in the ion distribution is explained on the basis of the cancellation of association entropy for ion-side chain pairs of opposite-charge and like-charge characters, which have positive and negative contributions, respectively. The C-terminal helix is observed to partially melt whereas a short beta strand forms at the higher temperature with little salt dependence. The N-terminal region, by contrast, develops partial helical structure at a higher salt concentration. These observed behaviors are consistent with solvent and salt screening playing an important role in stabilizing the canonical chemokine fold of hLtn.

Chlorides↗
PubMed2002

Molecular dynamics simulations of protein folding from the transition state.

Putative transition-state ensemble (TSE) conformations of src SH3 were identified by monitoring the deviation from the experimental phi values along molecular dynamics (MD) simulations of unfolding. Sixty MD trajectories (for a total of about 7 micros) were then started from the putative TSE. About one-half of the 60 runs reached the folded state while unfolding was observed in the remaining half of the runs. This result validates phi-value analysis as an approach to obtain structural information on the transition state. It also demonstrates that an atomic resolution description of the TSE can be extracted from MD simulations. All conformations in the TSE have the central three-stranded beta-sheet formed in agreement with experimental data. An elongation of strand beta 2 as well as non-native side-chain interactions between the diverging turn and the distal hairpin are observed. The simulation results indicate that the tight packing of the side chains between the diverging turn and the distal hairpin is a necessary condition for rapid folding. Contacts between residues in the most structured element of the TSE, the central beta-sheet, are kinetically more important than those between the N- and C-terminal strands.

Computer Simulation↗
PubMed1998

Effects of counter-ions and volume on the simulated dynamics of solvated proteins. Application to the activation domain of procarboxypeptidase B.

Molecular dynamics (MD) simulations of the globular activation domain of porcine procarboxypeptidase B (ADBp) and its isolated alpha-helix 1 were performed in order to understand the effects of adding salts and using periodic boundary conditions (this being reflected in the box size) along the simulations. alpha-Helix 1 was chosen because it is the most charged element of the secondary structure within ADBp. Different types of MD simulations with the GROMOS package were performed, studying either the whole activation domain or the isolated alpha-helix 1 with different water box sizes and counter-ionic shells. The analyses of the trajectories show that simulations of solvated proteins are highly sensitive to the presence of counter-ions and less sensitive to the volume of the water box. The differences in protein potential energies, r.m.s. deviations and radius of gyration between the simulations with and without counter-ions demonstrate that during such studies secondary structures of proteins are more stable when their charges are carefully neutralized. This stresses the need for such a procedure when analysing significantly charged proteins. The results also showed that the enlargement of the water box helps in the stabilization of the system.

Amino Acids↗
PubMed1997

Comparison of a left-handed Z-DNA molecular structure determined by X-rays with that simulated by a molecular dynamics.

The 1.0 A resolution X-ray crystal structures of the left-handed Z-DNA(Z-I and Z-II conformations) were compared with that of the simulated molecular dynamics(MD) structure both in vacuo and in solution. Whilst the X-ray structure showed a tendency for the d(CG)3 molecule to take on a Z-II conformation in high salt solution or in strongly ionized conditions, the MD simulation with Na ion for 30 ps revealed that the left-handed d(CG)3 structure with the Z-I conformation was transformed into the Z-II conformation in the torsion angles of the C3, G4 and C5 phosphate groups, and furthermore, when K+ ion was used as the counterion instead of Na+ ion, the torsion angles in almost the entire d(CG)3 molecule were preserved. On the other hand, the MD calculation resulted in some very important changes on the sugar puckerings; the simulation with Na+ ion indicated that all the sugar puckerings of cytosine residues were changed from C2'-endo to C3'-endo, while those for guanosine residues tended to keep unchanged (C3'-endo) except for a terminal residue (G6).

Crystallization↗
PubMed1998

A molecular simulation picture of DNA hydration around A- and B-DNA.

Recent results from molecular dynamics (MD) simulations on hydration of DNA with respect to conformation are reviewed and compared with experimental data. MD simulations of explicit solvent around DNA can now give a detailed model of DNA that not only matches well with the experimental data but provides additional insight beyond current experimental limitations. Such simulation results are analyzed with a focus on differential hydration properties between A- and B-DNA and between C/G and A/T base pairs. The extent of hydration is determined from the number of waters in the primary shell and compared to experimental numbers from different measurements. High-resolution hydration patterns around the whole DNA are shown and correlated with the conformations. The role of ions associating with DNA is discussed with respect to changes in the hydration structure correlating with DNA conformation.

Animals↗
PubMed1998

Barstar has a highly dynamic hydrophobic core: evidence from molecular dynamics simulations and nuclear magnetic resonance relaxation data.

The dynamic behavior of the ribonuclease inhibitor barstar has been investigated by molecular dynamics (MD) simulations in explicit water. Two 2.5 ns MD simulations were performed, and an ensemble of 25 000 structures was generated. This ensemble reproduces the solution structures and is consistent with the experimental structural restraints from NMR spectroscopy. Reorientation of the backbone NH bond vectors and side chain methyl groups was monitored by calculation of autocorrelation functions and the generalized S2 order parameters. Order parameters derived for motion in the approximately 100 ps time scale were compared with those obtained from NMR relaxation measurements. Consistent with experiment, the backbone NH bond vectors were relatively rigid. In contrast, the side chain methyl groups exhibited a wide dynamic range, from restricted motion comparable to that of the backbone to rapid unrestricted motion. The order parameters for the methyl groups correlate well with their spatial separation from the backbone and are residue-type dependent. Smaller S2axis values were observed for leucine methyl groups, in part due to side chain hopping between two predominant rotamers (g+t and tg-). Motions such as the flipping of aromatic rings and the hopping of leucine side chains were prevalent within the hydrophobic core, suggesting that the core is fluid-like with low energy barriers between native conformational substates. Thus, our studies suggest that the entropy of the native state can be significant and should not be discounted in thermodynamic considerations of protein folding. On the basis of our results, the side chain motion represents the primary source of the residual entropy of the native state and entropic considerations based solely on backbone dynamics would be incomplete.

Bacillus↗
PubMed2004

Ion motions in molecular dynamics simulations on DNA.

Counterions play a significant role in DNA structure and function, and molecular dynamics (MD) simulations offer the prospect of detailed description of the dynamical structure of ions at the molecular level. However, the motions of mobile counterions are notably slow to converge in MD on DNA. Obtaining accurate and reliable MD simulations requires knowing just how much sampling is required for convergence of each of the properties of interest. To address this issue, MD on a d(CGCGAATTCGCG) duplex in a dilute aqueous solution of water and 22 Na+ counterions was performed until convergence was achieved. The calculated first shell ion occupancies and DNA-Na+ radial distribution functions were computed as a function of time to assess convergence, and compared with relaxation times of the DNA internal parameters shift, slide, rise, tilt, roll, and twist. The sequence dependence of fractional occupancies of ions in the major and minor grooves of the DNA is examined, and the possibility of correlation between ion proximity and DNA minor groove widths is investigated.

Computer Simulation↗
PubMed2004

A force-field description of short-range repulsions for high density alkane molecular dynamics simulations.

The use of Buckingham (exp-6) van der Waals potentials in molecular dynamics (MD) simulations can quite successfully reproduce experimental thermodynamic data at low densities. However, they are less successful in producing a description of the repulsive regions of the potential energy surface (PES) that is in accord with the results of high-level ab initio computations. We show that Morse potentials can be parameterized to give excellent fits to both the attractive and repulsive regions of the PES. The best set of alkane van der Waals Morse function parameters reported to date for the description of nonbond repulsive interactions is presented, as determined by comparison with both ab initio and experimental results. C...C, H...H and C...H atom-pair potentials employing parameter sets based on the use of the geometric mean in the fitting procedure are found to be portable from methane to n-butane. Fitting to a combination of methane dimer interaction energies and forces from ab initio calculations yields parameter sets whose performance is superior to those determined from the interaction energies alone. Used in MD simulations, our newly developed parameter sets predict thermodynamic functions that show better agreement with experiment than those based on parameter sets in common use.

Journal Article↗
PubMed2005

Comparison of density functional theory and simulation of fluid bilayers.

We compare results of classical density functional theory (DFT) to molecular dynamics (MD) simulations of coarse-grained models of lipids in solvent. We find that the DFT captures the liquid structure of coarse-grained lipids both near surfaces and in bilayers adequately. In contrast we find that the MD simulations do not predict ordering in bilayers as is observed in low temperature DFT calculations. The mechanical properties of the fluid DFT bilayers are qualitatively similar to those of the MD bilayers; in particular the shapes of the lateral stress profiles are similar. Values of the area compressibility modulus are in reasonable agreement with previous work on coarse-grained lipids.

Computer Simulation↗
PubMed2005

Ensemble versus single-molecule protein unfolding.

Molecular dynamics (MD) simulations are the classic single-molecule "experiments," providing atomic-resolution structural and dynamic information. However, the single-molecule nature of the technique has also been its shortcoming, with frequent criticisms of sampling inadequacies and questions regarding the ensemble behavior of large numbers of molecules. Given the increase in computer power, we now address this issue by performing a large number of simulations and comparing individual and ensemble properties. One hundred independent MD simulations of the protein chymotrypsin inhibitor 2 were carried out for 20 ns each at 498 K in water to more fully describe the potentially diverse routes of protein unfolding and investigate how representative a single trajectory can be. Rapid unfolding was observed in all cases with the trajectories distributed about an average "ensemble" path in which secondary and tertiary structure was lost concomitantly, with tertiary structure loss occurring slightly faster. Individual trajectories did, however, sample conformations far from the average path with very heterogeneous time-dependent properties. Nevertheless, all of the simulations but one followed the average ensemble pathway, such that a small number of simulations (5-10) are sufficient to capture the average properties of these states and the unfolding pathway.

Hydrogen Bonding↗
PubMed2005

Neutron diffraction and computer simulation studies of D-xylose.

Neutron diffraction with isotopic substitution (NDIS) experiments and molecular dynamics (MD) simulations have been used to examine the pentose D-xylose in aqueous solution. By specifically labeling D-xylose molecules with a deuterium atom at the nonexchangeable hydrogen position on C4, it was possible to extract information about the atomic structuring around just that specific position. The MD simulations were found to give satisfactory agreement with the experimental NDIS results and could be used to help interpret the scattering data in terms of the solvent structuring as well as the intramolecular hydroxyl conformations. Although the experiment is challenging and on the limit of modern instrumentation, it is possible by careful analysis, in conjunction with MD studies, to show that the conformation trans to H4 at 180 degrees is strongly disfavored, in excellent agreement with the MD results. This is the first attempt to use NDIS experiments to determine the rotameric conformation of a hydroxyl group.

Carbohydrate Conformation↗
PubMedDate not supplied

Symplectic molecular dynamics simulations on specially designed parallel computers.

We have developed a computer program for molecular dynamics (MD) simulation that implements the Split Integration Symplectic Method (SISM) and is designed to run on specialized parallel computers. The MD integration is performed by the SISM, which analytically treats high-frequency vibrational motion and thus enables the use of longer simulation time steps. The low-frequency motion is treated numerically on specially designed parallel computers, which decreases the computational time of each simulation time step. The combination of these approaches means that less time is required and fewer steps are needed and so enables fast MD simulations. We study the computational performance of MD simulation of molecular systems on specialized computers and provide a comparison to standard personal computers. The combination of the SISM with two specialized parallel computers is an effective way to increase the speed of MD simulations up to 16-fold over a single PC processor.

Algorithms↗
PubMed1996

Molecular dynamics simulations of peptides from BPTI: a closer look at amide-aromatic interactions.

Molecular dynamics (MD) simulations of short peptides in water were performed to establish whether it is possible to reproduce experimental data from chemical shift measurements by nuclear magnetic resonance spectroscopy. Three different tetrapeptides were studied. The first, YTGP (Tyr-Thr-Gly-Pro), shows an electrostatic interaction between the aromatic ring of Tyr and the backbone amide hydrogen atom of Gly. The second, YTAP (Tyr-Thr-Ala-Pro), cannot make such an interaction because of steric hindrance of the Ala side chain and hence does not show a well-defined conformation. The third, FTGP (Phe-Thr-Gly-Pro), is shown to alternate between two different conformations. It is demonstrated that small differences in chemical shift, corresponding to these slightly different conformations, can be quantitatively modeled in MD simulations when using the proper force-field parameters and water model Explicit inclusion of hydrogen atoms o the aromatic rings is essential for a proper description of electrostatic interactions, but the choice of the water model is equally important. We found that a combination of the SPC/E water model and a revised GROMOS87 force field gives close agreement with experiment, while the same and other force fields in combination with SPC or TIP3P water did not reproduce the NMR data at all. Simulations of a longer peptide from bovine pancreatic trypsin inhibitor, containing the YTGP sequence, did show the interaction between the aromatic ring and the amide hydrogen, but not as pronounced as the simulations of shorter periods.

Amides↗
PubMed2003

New insights into the Jahn-Teller effect through ab initio quantum-mechanical/molecular-mechanical molecular dynamics simulations of CuII in water.

The CuII hydration shell structure has been studied by means of classical molecular dynamics (MD) simulations including three-body corrections and hybrid quantum-mechanical/molecular-mechanical (QM/MM) molecular dynamics (MD) simulations at the Hartree-Fock level. The copper(II) ion is found to be six-fold coordinated and [Cu(H2O)6]2+ exhibits a distorted octahedral structure. The QM/MM MD approach reproduces correctly the experimentally observed Jahn-Teller effect but exhibits faster inversions (< 200 fs) and a more complex behaviour than expected from experimental data. The dynamic Jahn-Teller effect causes the high lability of [Cu(H2O)6]2+ with a ligand-exchange rate constant some orders or magnitude higher than its neighbouring ions NiII and ZnII. Nevertheless, no first-shell water exchange occurred during a 30-ps simulation. The structure of the hydrated ion is discussed in terms of radial distribution functions, coordination numbers, and various angular distributions and the dynamical properties as librational and vibrational motions and reorientational times were evaluated, which lead to detailed information about the first hydration shell. Second-shell water-exchange processes could be observed within the simulation time scale and yielded a mean ligand residence time of approximelty 20 ps.

Journal Article↗