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PubMed2002

Molecular dynamics simulation of dipalmitoylphosphatidylserine bilayer with Na+ counterions.

We performed a molecular dynamics simulation of dipalmitoylphosphatidylserine (DPPS) bilayer with Na+ counterions. We found that hydrogen bonding between the NH group and the phosphate group leads to a reduction in the area per headgroup when compared to the area in dipalmitoylphosphatidylcholine bilayer. The Na+ ions bind to the oxygen in the carboxyl group of serine, thus giving rise to a dipolar bilayer similar to dipalmitoylphosphatidylethanolamine bilayer. The results of the simulation show that counterions play a crucial role in determining the structural and electrostatic properties of DPPS bilayer.

Biophysical Phenomena↗

PubMed2000

Homology modeling and molecular dynamics simulations of lymphotactin.

We have modeled the structure of human lymphotactin (hLpnt), by homology modeling and molecular dynamics simulations. This chemokine is unique in having a single disulfide bond and a long C-terminal tail. Because other structural classes of chemokines have two pairs of Cys residues, compared to one in Lpnt, and because it has been shown that both disulfide bonds are required for stability and function, the question arises how the Lpnt maintains its structural integrity. The initial structure of hLpnt was constructed by homology modeling. The first 63 residues in the monomer of hLpnt were modeled using the structure of the human CC chemokine, RANTES, whose sequence appeared most similar. The structure of the long C-terminal tail, missing in RANTES, was taken from the human muscle fatty-acid binding protein. In a Protein Data Bank search, this protein was found to contain a sequence that was most homologous to the long tail. Consequently, the modeled hLpnt C-terminal tail consisted of both alpha-helical and beta-motifs. The complete model of the hLpnt monomer consisted of two alpha-helices located above the five-stranded beta-sheet. Molecular dynamics simulations of the solvated initial model have indicated that the stability of the predicted fold is related to the geometry of Pro78. The five-stranded beta-sheet appeared to be preserved only when Pro78 was modeled in the cis conformation. Simulations were also performed both for the C-terminal truncated forms of the hLpnt that contained one or two (CC chemokine-like) disulfide bonds, and for the chicken Lpnt (cLpnt). Our MD simulations indicated that the turn region (T30-G34) in hLpnt is important for the interactions with the receptor, and that the long C-terminal region stabilizes both the turn (T30-G34) and the five-stranded beta-sheet. The major conclusion from our theoretical studies is that the lack of one disulfide bond and the extension of the C-terminus in hLptn are mutually complementary. It is very likely that removal of two Cys residues sufficiently destabilizes the structure of a chemokine molecule, particularly the core beta-sheet, to abolish its biological function. However, this situation is rectified by the long C-terminal segment. The role of this long region is most likely to stabilize the first beta-turn region and alpha-helix H1, explaining how this chemokine can function with a single disulfide bond.

Amino Acid Sequence↗

PubMed1997

Hydration of the dTn.dAn x dTn parallel triple helix: a Fourier transform infrared and gravimetric study correlated with molecular dynamics simulations.

We present a comparative analysis of the water organization around the dTn.dAn x dTn triple helix and the Watson-Crick double helix dTn.dAn respectively by means of gravimetric measurements, infrared spectroscopy and molecular dynamics simulations. The hydration per nucleotide determined by gravimetric and spectroscopic methods correlated with the molecular dynamics simulations shows that at high relative humidity (98% RH) the triple helix is less solvated than the duplex (17 +/- 2 water molecules per nucleotide instead of 21 +/-1). The experimental desorption curves are different for both structures and indicate that below 81% RH the triplex becomes more hydrated than the duplex. At this RH the FTIR spectra show the emergence of N-type sugars in the adenosine strand of the triplex. When the third strand is bound in the major groove of the Watson-Crick duplex molecular dynamics simulations show the formation of a spine of water molecules between the two thymidine strands.

DNA↗

PubMed2004

Large-scale molecular dynamics simulations of alkanethiol self-assembled monolayers.

Large-scale molecular dynamics simulations of self-assembled alkanethiol monolayer systems have been carried out using an all-atom model involving a million atoms to investigate their structural properties as a function of temperature, lattice spacing, and molecular chain length. Our simulations show that the alkanethiol chains of 13-carbons tilt from the surface normal by a collective angle of 25 degrees along next-nearest-neighbor direction at 300 K. The tilt structure of 13-carbon alkanethiol system is found to depend strongly on temperature and exhibits hysteresis. At 350 K the 13-carbon alkanethiol system transforms to a disordered phase characterized by small collective tilt angle, flexible tilt direction, and random distribution of backbone planes. The tilt structure also depends on lattice spacing: With increasing lattice spacing a the tilt angle increases rapidly from a nearly zero value at a=4.7 A to as high as 34 degrees at a=5.3 A at 300 K for 13-carbon alkanethiol system. Finally, the effects of the molecular chain length on the tilt structure are significant at high temperatures.

Alkanes↗

PubMedDate not supplied

[Generalized ordering parameter S2 for N-H peptide bonding as measure of the conformational flexibility of proteins: comparison of algorithms of S2 calculation from molecular dynamics simulation data].

NMR spectroscopy in combination with molecular dynamics (MD) simulation technique is a powerful tool for investigation of biomolecule conformations. In the present study we compare the two algorithms of calculation of the generalized order parameter S2 for the peptide N-H bond from MD simulation data. The program based on this algorithm has been written and the effect of an adjustible parameter on results of calculation was studied. HIV-1 protease MD simulation was performed during 7.36 ns using GROMACS 3.1.4. software package. The calculated order parameter values are in good agreement with those obtained by other authors using NMR.

Algorithms↗

PubMed2006

Identification of isolated cavity features within molecular dynamics simulated chromatographic surfaces.

Highly ordered morphological features were characterized for molecular dynamics simulated alkyl-modified silica models that represent chromatographic materials with enhanced shape recognition capability. Deep cavities (8-10A wide) within the alkyl chains were identified for C18 polymeric models corresponding to shape-selective RPLC stationary phases. The all-trans conformational distal-end segments of these isolated cavities averaged over a 100 ps simulation time interval were observed to increase (up to 15 A) in models with an increase in both surface coverage and corresponding shape selectivity. Similar-structure cavities with significant alkyl chain ordered regions (>11A) were isolated from two independent C18 models (differing in bonding chemistry, density and temperature) that represent highly shape-selective materials. The size and depth of these ordered regions increased (up to 28 A) for the extended-length C30 alkyl phase models. These initial results offer a physical representation of alkyl-modified surfaces that may facilitate the identification of potential molecular features that may be involved in the shape-selective retentive processes, as well as illustrating the potential for such computational techniques to predict the molecular recognition capabilities of novel analyte-specific sorbents.

Adsorption↗

PubMed2003

Analysis of the effect of electrostatic energy truncation in molecular dynamics simulations of immunoglobulin G light chain dimer.

Molecular dynamics (MD) simulations of immunoglobulin G (IgG) light chain dimer using particle mesh Ewald (PME) and cutoff methods of treating electrostatic interactions were performed. The results indicate that structural parameters (RMSD, radius of gyration, solvent accessible surface) are very similar for both schemes; however, PME simulation shows increased mobility of side chains. This leads to larger fluctuations in the distance between the monomers in the dimer molecule, and, as a consequence, results in decreased number of interactions across the dimer interface. The wall clock time of the simulations was also compared. It was shown that the PME method is approximately 30% faster than the cutoff method for the system studied on a single processor.

Computer Simulation↗

PubMed1998

Molecular dynamics simulations of DNA in solutions with different counter-ions.

Molecular dynamics simulations of the [d(ATGCAGTCAG]2 fragment of DNA, in water and in the presence of three different counter-ions (Li+, Na+ and Cs+) are reported. Three-dimensional hydration structure and ion distribution have been calculated using spatial distribution functions for a detailed picture of local concentrations of ions and water molecules around DNA. According to the simulations, Cs+ ions bind directly to the bases in the minor groove, Na+ ions bind prevailing to the bases in the minor groove through one water molecule, whereas Li+ ions bind directly to the phosphate oxygens. The different behavior of the counter-ions is explained by specific hydration structures around the DNA and the ions. It is proposed how the observed differences in the ion binding to DNA may explain different conformational behavior of DNA. Calculated self-diffusion coefficients for the ions agree well with the available NMR data.

Cesium↗

PubMed2006

Peptide-TiO2 surface interaction in solution by ab initio and molecular dynamics simulations.

Ab initio periodic calculations and classical molecular dynamics (MD) simulations were performed to investigate the adsorption mode of alanine and a number of short peptides, in particular two peptides, alanine-glutamic acid and alanine-lysine, taken as model systems for the ionic self-complementary oligopeptide EAK16-II, onto TiO(2) (110) rutile surface, and their conformational characteristics upon adsorption. The atomistic description of the rutile surface and its interactions with water and peptide molecules were based on ab initio calculations, the TIP3P water model, the AMBER force field, and available parameters. By comparison with ab initio calculations, it is shown that MD simulations of reasonable duration can describe the main characteristics of the peptide-TiO(2) surface interaction in solution, at least on a short time scale. Atom-atom radial distribution functions, atom-surface distances, backbone and side chain dihedral angle distributions, and peptide-surface interaction energies have been analyzed. Once adsorbed onto the TiO(2) rutile surface by a bidentate interaction of both carboxyl oxygens with two adjacent Ti atoms, the small peptide studied showed a clear propensity to remain there and undergo relatively limited hinge-bending motions.

Adsorption↗

PubMed1994

Molecular dynamics simulation and NMR study of a blood group H trisaccharide.

Molecular dynamics simulations in vacuum and solution have been carried out on 2'-alpha-L-fucosyl-lactitol, a model for blood group H in conjunction with two-dimensional nmr measurements on the same compound. Three independent starting conformations for the dynamics were chosen from low energy conformations obtained by a phi/psi grid search. Nine 5 ns vacuum simulations of the trisaccharide were performed, employing three different ways to treat electrostatic interactions for each starting conformation: distance-dependent dielectric with epsilon = r, constant dielectric with epsilon = 1, or constant dielectric with epsilon = 80. In vacuum, transitions of phi and psi for the alpha-L-Fuc-(1-->2)-beta-D-Gal element occur in a cooperative manner. The virtual distance obtained for H1 in fucose to H2 in galactose from nuclear Overhauser effect spectroscopy experiments agree with one of the conformations of the trisaccharide in one of the three 100 ps aqueous simulations (phi/psi ca. -100 degrees/150 degrees), indicating this may be a dominant solution conformation. The rms fluctuations of the phi- and psi-dihedral angles were approximately 10 degrees for a conformational state, both in the vacuum and the aqueous simulations. For the simulations in vacuum, the agreement with experimental NOE data is reasonable when a constant dielectric of 1 is used (major conformers having phi/psi ca. -100 degrees/150 degrees and -140 degrees/100 degrees), whereas the agreement was poor with a constant dielectric of 80. Translational diffusion coefficients calculated from the simulation of the oligosaccharides were 0.12-0.18 x 10(-5) cm2/s and from nmr measurements 0.27 x 10(-5) cm2/s.

ABO Blood-Group System↗

PubMed1999

Molecular dynamics simulations of supported phospholipid/alkanethiol bilayers on a gold(111) surface.

Molecular dynamics simulations have been used to investigate the structure of hybrid bilayers (HB) formed by dipalmitoylphosphatidylcholine (DPPC) lipid monolayers adsorbed on a hydrophobic alkanethiol self-assembled monolayer (SAM). The HB system was studied at 20 degrees C and 60 degrees C, and the results were compared with recent neutron reflectivity measurements (Meuse, C. W., S. Krueger, C. F. Majkrzak, J. A. Dura, J. Fu, J. T. Connor, and A. L. Plant. 1998. Biophys. J. 74:1388) and previous simulations of hydrated multilamellar bilayers (MLB) of DPPC (Tu, K., D. J. Tobias, and M. L. Klein. 1995. Biophys. J. 69:2558; and 1996. 70:595). The overall structures of the HBs are in very good agreement with experiment. The structure of the SAM monolayer is hardly perturbed by the presence of the DPPC overlayer. The DPPC layer presents characteristics very similar to the MLB gel phase at low temperature and to the liquid crystal phase at high temperature. Subtle changes have been found for the lipid/water interface of the HBs compared to the MLBs. The average phosphatidylcholine headgroup orientation is less disordered, and this produces changes in the electric properties of the HB lipid/water interface. These changes are attributed to the fact that the aqueous environment of the lipids in these unilamellar films is different from that of MLB stacks. Finally, examination of the intramolecular and whole-molecule dynamics of the DPPC molecules in the fluid phase HB and MLB membranes revealed that the reorientations of the upper part of the acyl chains (near the acyl ester linkage) are slower, the single molecule protrusions are slightly damped, and the lateral rattling motions are significantly reduced in the HB compared with the MLB.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1995

Molecular dynamics simulation of fungal cellulose-binding domains: differences in molecular rigidity but a preserved cellulose binding surface.

A total of 23 fungal cellulose-binding domain (CBD) sequences were aligned. Structural models of the cellulose-binding domain of an exoglucanase (CBHII) and of three endoglucanases (EGI, EGII and EGV) from Trichoderma reesei cellulases were homology modelled based on the NMR structure of the fungal cellobiohydrolase CBHI, from the same organism. The completed models and the known structure of the CBHI cellulose-binding domain were refined by molecular dynamics simulations in water. All four models were found to be very similar to the structure of the CBHI cellulose-binding domain and sequence comparison indicated that in general the three-dimensional structures of fungal cellulose-binding domains are very similar. In all the CBDs studied, two disulphide bridges apparently stabilize the polypeptide fold. From the models, and additional disulphide bridge was predicted in EGI and CBHII, and in eight further CBDs from other organisms. Three highly conserved aromatic residues on the hydrophilic side of the wedge make this surface flat. This surface is expected to make contact with the substrate. Three invariant amino acids, Gln7, Asn29 and Gln34, on this flat face are in suitable positions for hydrogen bonding with the cellulose surface. Analysis of the differences in the protein surface properties indicated that the endoglucanases tend to be more hydrophilic than the exoglucanases. The largest structural variation was found around positions 12-16. The fungal CBD sequences are discussed in relation to variations in function and pH dependence. Comparison of the modelled structures with experimental binding data for the CBHI and EGI allowed the formulation of a qualitative relationship to cellulose affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2003

Comparison of various implicit solvent models in molecular dynamics simulations of immunoglobulin G light chain dimer.

The present study tests performance of different solvation models applied to molecular dynamics simulation of a large, dimeric protein molecule. Analytical Continuum Electrostatics (ACE) with two different parameter sets, older V98 and new V01, and Effective Energy Function (EEF) are employed in molecular dynamics simulation of immunoglobulin G (IgG) light chain dimer and variable domain of IgG light chain. Results are compared with explicit solvent and distance dependent dielectric constant (DDE) calculations. The overall analysis shows that the EEF method yields results comparable to explicit solvent simulations; however, the stability of simulations is lower. On the other hand, the ACE_V98 model does not seem to achieve the accuracy or stability expected in nanosecond timescale MD simulation for the studied systems. The ACE_V01 model greatly improves stability of the calculation; nonetheless, changes in radius of gyration and solvent accessible surface of the studied systems may indicate that the parameter set still needs to be improved if the method is supposed to be used for simulations of large, polymeric proteins. Additionally, electrostatic contribution to the solvation free energy calculated in the ACE model is compared with a numerical treatment of the dielectric continuum model. Wall clock time of all simulations is compared. It shows that EEF calculation is six times faster than corresponding ACE and 50 times faster than explicit solvent simulations.

Computer Simulation↗

PubMed2004

DL_POLY_3: the CCP5 national UK code for molecular-dynamics simulations.

DL_POLY_3 is a general-purpose molecular-dynamics simulation package embedding a highly efficient domain decomposition (DD) parallelization strategy. It was developed at Daresbury Laboratory under the auspices of the Engineering and Physical Sciences Research Council. Written to support academic research, it has a wide range of applications and will run on a wide range of computers; from single-processor workstations to multi-processor computers, with accent on the efficient use of multi-processor power. A new DD adaptation of the smoothed particle mesh Ewald method for calculating long-range forces in molecular simulations, incorporating a novel three-dimensional fast Fourier transform (the Daresbury Advanced Fourier Transform), makes it possible to simulate systems of the order of one million particles and beyond. DL_POLY_3 structure, functionality, performance and availability are described in this feature paper.

Algorithms↗

PubMed1994

Determination of the backbone mobility of ribonuclease T1 and its 2'GMP complex using molecular dynamics simulations and NMR relaxation data.

The results of 1-nanosecond molecular dynamics simulations of the enzyme ribonuclease T1 and its 2'GMP complex in water are presented. A classification of the angular reorientations of the backbone amide groups is achieved via a transformation of NH-vector trajectories into several coordinate frames, thus unravelling contributions of NH-bond librations and backbone dihedral angle fluctuations. The former turned out to be similar for all amides, as characterized by correlation times of librational motions in a subpicosecond scale, angular amplitudes of about 10-12 degrees for out-of-peptide-plane displacements of the NH-bond and 3-5 degrees for the in-plane displacements, whereas the contributions of much slower backbone dihedral angle fluctuations strongly depend on the secondary structure. Correlation functions relevant for NMR were obtained and analyzed utilizing the 'model-free' approach (Lipari, G. and Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559, 4559-4570; Clore et al., (1990) J. Am. Chem. Soc. 112, 4989-4991). The dependence of the amplitude of local motion on the residue location in the backbone is in good agreement with the results of NMR relaxation measurements and X-ray data. The protein dynamics is characterized by a highly restricted local motion of those parts of the backbone with defined secondary structure as well as by a high flexibility in loop regions. The comparison of results derived from different periods of the trajectory (of 50 ps and 1 ns duration, 1000 points sampled) reveals a dependence of the observed dynamic picture on the characteristic time scale of the experimental method used. Comparison of the MD data for the free and liganded enzyme clearly indicates a restriction of the mobility within certain regions of the backbone upon inhibitor binding.

Computer Simulation↗

PubMed1988

Importance of folded monomer and extended antiparallel dimer structures as enkephalin active conformation. Molecular dynamics simulations of [Met5]enkephalin in water.

Simulations of the molecular dynamics of the [Met5]enkephalin monomer and dimer structures in water have been carried out. The dynamic trajectories have been analyzed in terms of the distances between intra- or intermolecular polar atoms. The time-correlated conformational transitions of an extended monomer structure have been converged into a stationary state among the beta-bend folded forms. However, the dynamics simulation of an extended antiparallel dimer structure has shown no noticeable conformation change. These results imply that both the beta-bend monomer and the extended dimer structures exist together as the fundamental conformation of enkephalins.

Calorimetry↗

PubMed1995

Molecular dynamics simulations of m3-muscarinic receptor activation and QSAR analysis.

Molecular dynamics simulations of the rat m3-muscarinic seven-helix-bundle receptor models were performed on the free, agonist-bound and antagonist-bound forms. A comparative structural/dynamics analysis was performed in order to explain the perturbations induced by the functionally different ligands when binding to their target receptor. Theoretical quantitative structure-activity relationship models were developed; a good correlation was obtained between the interaction energies of the minimized average ligand-receptor complexes and the pharmacological affinities of the considered ligands. The consistency obtained between the structural rearrangement of the transmembrane seven-helix-bundle models considered and the experimental pharmacological efficacies and affinities of the ligands constitutes an important validation of the 3-D models proposed and allows the inference of the mechanism of ligand-induced or mutation-induced receptor activation at the molecular level.

Animals↗

PubMed1996

Rational choice of molecular dynamics simulation parameters through the use of the three-dimensional autocorrelation method: application to calmodulin flexibility study.

We examined the effects of several adjustable parameters for use in molecular dynamics simulations of proteins using both standard criteria (radius of gyration, root mean square deviation from starting coordinates, molecular mechanics energy) and a new description of protein conformations by 3-D autocorrelation vectors (3-D ACV). We chose calmodulin (CaM) as a protein model and analysed 23 simulations using different combinations of the four molecular dynamics parameters studied, such as the dielectric constant (epsilon), the heating phase time (H), the thermal bath coupling time (zeta T) and the time step size (delta t). The correctness of the various trajectories generated with different parameter sets was evaluated through geometric analysis and use of a knowledge-based profile method. It is shown that 3-D ACV combined with multivariate statistical analysis provides a convenient way to describe and compare molecular dynamics simulations and constitutes a valuable complementary tool to standard methods. Using these methods, comparison of the various simulations performed on CaM indicated that the best in vacuo parameter set was epsilon = 1 x r, H = 15 ps, zeta T = 0.1 ps and delta t = 1 fs in fairly good agreement with previous less extensive comparisons of molecular dynamics trajectories.

Binding Sites↗