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At least 883 records · Page 49Linked to original sources
PubMed2004

Molecular dynamics simulations of the human CAR ligand-binding domain: deciphering the molecular basis for constitutive activity.

The constitutive androstane receptor (CAR) belongs to the superfamily of nuclear-hormone receptors that function as ligand-activated transcription factors. CAR plays an essential role in the metabolism of xenobiotics and shows--in contrast to related receptors--constitutive activity. However, the molecular basis for the constitutive activity remains unclear. In the present study, homology models of the ligand binding domain (LBD) were generated based on the crystal structures of the related pregnane X (PXR) and the vitamin D receptor (VDR). The models were used to investigate the basal activity of CAR and the effect of coactivator binding. Molecular dynamics (MD) simulations of complexed and uncomplexed receptor revealed a hypothesis for the activation mechanism. The suggested mechanism is supported by experimental results from site-directed mutagenesis. The basal activity of CAR can be explained by specific van-der-Waals interactions between amino acids on the LBD and its C-terminal activation domain (AF-2). Docking studies with the GOLD program yielded the interaction modes of structurally diverse agonists, giving insight into mechanisms by which ligands enhance CAR activity.

Amino Acid Sequence↗
PubMed2003

Molecular dynamics simulations of a silver atom in water: evidence for a dipolar excitonic state.

The properties of a silver atom in bulk water were studied for the first time by molecular dynamics simulations using two complementary mixed quantum-classical approaches. The first one consists of treating by quantum mechanics one electron only, which interacts with a classical silver cation and solvent through one-electron pseudopotentials. The second one is Car-Parrinello molecular dynamics that treats all the valence electrons quantum-mechanically. Very good agreement is obtained between these two methods, and the calculated absorption spectrum of the solvated silver atom agrees very well with experimental data. Both simulations reveal that the silver atom is in the critical region for the appearance of a dipolar excitonic state and exhibits a dipole moment of approximately 2 D with large fluctuations of +/-1 D. The structure of the solvation shell is also analyzed.

Journal Article↗
PubMed1995

A one nanosecond molecular dynamics simulation of the glucocorticoid receptor protein in complex with a glucocorticoid response element DNA sequence in a 10 Angstrom water layer.

We investigated protein/DNA interactions, using molecular dynamics simulations computed for one nanosecond, between a 10 Angstom water layer model of the glucocorticoid receptor (GR) DNA binding domain (DBD) amino acids and DNA of a glucocorticoid receptor response element (GRE) consisting of 29 nucleotide base pairs. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Amino acids of the GR DBD DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon-anticodon nucleotide base and backbone sites within the GRE DNA right major groove halfsite. Likewise amino acids in a beta strand structure adjacent to the DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon-anticodon nucleotide base and backbone sites within both the GRE right and left major groove halfsites. In addition, amino acids within a predicted alpha helix located on the carboxyl terminus of the GR DBD interacted at codon-anticodon nucleotide sites on the DNA backbone of the GRE right major groove flanking nucleotides. These interactions together induced breakage of Watson-Crick nucleotide base pairing hydrogen bonds, resulting in significant structural changes and bending of the DNA into the protein.

Amino Acids↗
PubMed1998

Molecular dynamics simulation of melittin in a dimyristoylphosphatidylcholine bilayer membrane.

Molecular dynamics trajectories of melittin in an explicit dimyristoyl phosphatidylcholine (DMPC) bilayer are generated to study the details of lipid-protein interactions at the microscopic level. Melittin, a small amphipathic peptide found in bee venom, is known to have a pronounced effect on the lysis of membranes. The peptide is initially set parallel to the membrane-solution interfacial region in an alpha-helical conformation with unprotonated N-terminus. Solid-state nuclear magnetic resonance (NMR) and polarized attenuated total internal reflectance Fourier transform infrared (PATIR-FTIR) properties of melittin are calculated from the trajectory to characterize the orientation of the peptide relative to the bilayer. The residue Lys7 located in the hydrophobic moiety of the helix and residues Lys23, Arg24, Gln25, and Gln26 at the C-terminus hydrophilic form hydrogen bonds with water molecules and with the ester carbonyl groups of the lipids, suggesting their important contribution to the stability of the helix in the bilayer. Lipid acyl chains are closely packed around melittin, contributing to the stable association with the membrane. Calculated density profiles and order parameters of the lipid acyl chains averaged over the molecular dynamics trajectory indicate that melittin has effects on both layers of the membrane. The presence of melittin in the upper layer causes a local thinning of the bilayer that favors the penetration of water through the lower layer. The energetic factors involved in the association of melittin at the membrane surface are characterized using an implicit mean-field model in which the membrane and the surrounding solvent are represented as structureless continuum dielectric material. The results obtained by solving the Poisson-Bolztmann equation numerically are in qualitative agreement with the detailed dynamics. The influence of the protonation state of the N-terminus of melittin is examined. After 600 ps, the N-terminus of melittin is protonated and the trajectory is continued for 400 ps, which leads to an important penetration of water molecules into the bilayer. These observations provide insights into how melittin interacts with membranes and the mechanism by which it enhances their lysis.

Amino Acid Sequence↗
PubMed2005

Nematic-isotropic interfaces under shear: a molecular-dynamics simulation.

We present a large-scale molecular-dynamics study of nematic-paranematic interfaces under shear. We use a model of soft repulsive ellipsoidal particles with well-known equilibrium properties, and consider interfaces which are oriented normal to the direction of the shear gradient (common stress case). The director at the interface is oriented parallel to the interface (planar). A fixed average shear rate is imposed with moving periodic boundary conditions, and the heat is dissipated with a profile-unbiased thermostat. First, we study the properties of the interface at one particular shear rate in detail. The local interfacial profiles and the capillary wave fluctuations of the interfaces are calculated and compared with those of the corresponding equilibrium interface. Under shear, the interfacial width broadens and the capillary wave amplitudes at large wavelengths increase. The strain is distributed inhomogeneously in the system (shear banding), the local shear rate in the nematic region being distinctly higher than in the paranematic region. Surprisingly, we also observe (symmetry-breaking) flow in the vorticity direction, with opposite direction in the nematic and the paranematic state. Finally, we investigate the stability of the interface for other shear rates and construct a nonequilibrium phase diagram.

Journal Article↗
PubMed2006

Molecular dynamics simulations of ballistic annihilation.

Using event-driven molecular dynamics we study one- and two-dimensional ballistic annihilation. We estimate exponents xi and gamma, which describe the long-time decay of the number of particles [n(t) approximately t-xi] and of their typical velocity [v(t) approximately t-gamma]. To a good accuracy our results confirm the scaling relation xi+gamma=1. In the two-dimensional case our results are in good agreement with those obtained from Boltzmann kinetic theory.

Journal Article↗
PubMed1999

Docking of flexible ligands to flexible receptors in solution by molecular dynamics simulation.

In this paper, a method of simulating the docking of small flexible ligands to flexible receptors in water is reported. The method is based on molecular dynamics simulations and is an extension of an algorithm previously reported by Di Nola et al. (Di Nola et al., Proteins 1994;19:174-182). The method allows a fast exploration of the receptor surface, using a high temperature of the center of mass translational motion, while the ligand internal motions, the solvent, and the receptor are simulated at room temperature. In addition, the method allows a fast center of mass motion of the ligand, even in solution. The dampening effect of the solvent can be overcome by applying different weights to the interactions between system subsets (solvent, receptor, and ligand). Specific ligand-receptor distances have been used to compare the results of the simulations with the crystal structure. The method is applied, as a test system, to the docking of the phosphocholine to the immunoglobulin McPC603. The results show the similarity of structure between the complex in solution and in the crystal.

Algorithms↗
PubMed1998

Reversible peptide folding in solution by molecular dynamics simulation.

Long-standing questions on how peptides fold are addressed by the simulation at different temperatures of the reversible folding of a peptide in solution in atomic detail. Molecular dynamics simulations correctly predict the structure that is thermodynamically stable at 298 K, irrespective of the initial peptide conformation. The rate of folding and the free energy of folding at different temperatures are estimated. Although the conformational space potentially accessible to the peptide is extremely large, very few conformers (10(1) to 10(2)) are significantly populated at 20 K above the melting temperature. This implies that the search problem in peptide (or even protein) folding is surmountable using dynamics simulations.

Computer Simulation↗
PubMed1998

Adhesion forces of lipids in a phospholipid membrane studied by molecular dynamics simulations.

Lipid adhesion forces can be measured using several experimental techniques, but none of these techniques provide insight on the atomic level. Therefore, we performed extensive nonequilibrium molecular dynamics simulations of a phospholipid membrane in the liquid-crystalline phase out of which individual lipid molecules were pulled. In our method, as an idealization of the experimental setups, we have simply attached a harmonic spring to one of the lipid headgroup atoms. Upon retraction of the spring, the force needed to drag the lipid out of the membrane is recorded. By simulating different retraction rates, we were able to investigate the high pull rate part of the dynamical spectrum of lipid adhesion forces. We find that the adhesion force increases along the unbinding path, until the point of rupture is reached. The maximum value of the adhesion force, the rupture force, decreases as the pull rate becomes slower, and eventually enters a friction-dominated regime. The computed bond lengths depend on the rate of rupture, and show some scatter due to the nonequilibrium nature of the experiment. On average, the bond length increases from approximately 1.7 nm to 2.3 nm as the rates go down. Conformational analyses elucidate the detailed mechanism of lipid-membrane bond rupture. We present results of over 15 ns of membrane simulations. Implications for the interpretation and understanding of experimental rupture data are discussed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

Self-assembling of peptide/membrane complexes by atomistic molecular dynamics simulations.

Model biological membranes consisting of peptide/lipid-bilayer complexes can nowadays be studied by classical molecular dynamics (MD) simulations at atomic detail. In most cases, the simulation starts with an assumed state of a peptide in a preformed bilayer, from which equilibrium configurations are difficult to obtain due to a relatively slow molecular diffusion. As an alternative, we propose an extension of reported work on the self-organization of unordered lipids into bilayers, consisting of including a peptide molecule in the initial random configuration to obtain a membrane-bound peptide simultaneous to the formation of the lipid bilayer. This strategy takes advantage of the fast reorganization of lipids, among themselves and around the peptide, in an aqueous environment. Model peptides of different hydrophobicity, CH3-CO-W2L18W2-NH2 (WL22) and CH3-CO-W2A18W2-NH2 (WA22), in dipalmitoyl-phosphatidylcholine (DPPC) are used as test cases. In the equilibrium states of the peptide/membrane complexes, achieved in time ranges of 50-100 ns, the two peptides behave as expected from experimental and theoretical studies. The strongly hydrophobic WL22 is inserted in a transmembrane configuration and the marginally apolar, alanine-based WA22 is found in two alternative states: transmembrane inserted or parallel to the membrane plane, embedded close to the bilayer interface, with similar stability. This shows that the spontaneous assembly of peptides and lipids is an unbiased and reliable strategy to produce and study models of equilibrated peptide/lipid complexes of unknown membrane-binding mode and topology.

Computer Simulation↗
PubMed2005

Molecular-dynamics simulations of cold antihydrogen formation in strongly magnetized plasmas.

Employing a high-order symplectic integrator and an adaptive time-step algorithm, we perform molecular-dynamics simulations of antihydrogen formation, in a cold plasma confined by a strong magnetic field, over time scales of microseconds. Sufficient positron-antiproton recombination events occur to allow a statistical analysis for various properties of the formed antihydrogen atoms. Giant-dipole states are formed in the initial stage of recombination. In addition to neutral atoms, we also observe antihydrogen positive ions (H(+)), in which two positrons simultaneously bind to an antiproton.

Journal Article↗
PubMed2026

Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties.

FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, FCGR1A, using codon-based selection tests on aligned 1-1 orthologous sequences from placental mammals (n = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H148 (M2a ω 0.997 & M8 ω = 0.993)) and (W149 (M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H148P and W149R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day Homo sapiens. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H148P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W149R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.

Receptors, IgG↗
PubMed2002

Thermal unfolding molecular dynamics simulation of Escherichia coli dihydrofolate reductase: thermal stability of protein domains and unfolding pathway.

Temperature induced unfolding of Escherichia coli dihydrofolate reductase was carried out by using molecular dynamic simulations. The simulations show that the unfolding generally involves an initial end-to-end collapse of the adenine binding domain into partially extended loops, followed by a gradual breakdown of the remaining beta sheet core structure. The core, which consists of beta strands 5-7, was observed to be the most resistant to thermal unfolding. This region, which is made up of part of the N terminus domain and part of the large domain of the E. coli dihydrofolate reductase, may constitute the nucleation site for protein folding and may be important for the eventual formation of both domains. The unfolding of different domains at different stages of the unfolding process suggests that protein domains vary in stability and that the rate at which they unfold can affect the overall outcome of the unfolding pathway. This observation is compared with the recently proposed hierarchical folding model. Finally, the results of the simulation were found to be consistent with a previous experimental study (Frieden, Proc Natl Acad Sci USA 1990;87:4413-4416) which showed that the folding process of E. coli dihydrofolate reductase involves sequential formation of the substrate binding sites.

Computer Simulation↗
PubMed2007

Contraction process of an electroactive actuator based on a one microsecond atomistic molecular dynamics simulation.

The contraction process of an electroactive actuator constituted by calix[4]arene units and quaterthiophene segments has been investigated at the microscopic level by using atomistic molecular dynamics simulations in dichloromethane solution using explicit solvent molecules. Results derived from a 1 mus trajectory of the oxidized and deprotonated actuator indicate that the contraction occurs through a non-concerted mechanism in which each actuating units present in the system behave independently. The efficiency of the contraction process can be reduced by the presence of secondary conformational transitions in the calix[4]arene scaffolds. Accordingly, the drastic reduction of the molecular length expected during the contraction process can be limited by such transitions, which involve the rotational isomerism of a phenolate ring. However, such type of conformational transitions does not compromise the actuator power due to its intrinsic capacity to adopt compact molecular arrangements. On the other hand, the rate of the contraction process is influenced by the presence of solvent molecules, which have been found to reduce it by a factor of about 1000.

Calixarenes↗
PubMed2006

Mass transport of O2 and N2 in nanoporous carbon (C168 schwarzite) using a quantum mechanical force field and molecular dynamics simulations.

A hierarchical approach is used to calculate the single-component fluxes of N2 and O2 in nanoporous carbon molecular sieves (represented by C168 schwarzite) over a wide range of pressures and pressure drops. The self- and corrected diffusivities are calculated using equilibrium molecular dynamics simulations with force fields for the gas-carbon interactions obtained from quantum mechanical calculations. These results are combined with previously reported adsorption isotherms of N2 and O2 in C168 to obtain transport diffusivities and, by use of the Fick's equation of mass transport, to obtain single-component fluxes across the membrane. The diffusion coefficients and fluxes are also calculated using an empirical potential, which has been obtained by fitting low coverage adsorption data of N2 and O2 on a planar graphite sheet. By analyzing the diffusivities calculated with the ab initio potential in the limit of infinite dilution over the temperature range from 80 to 450 K, it is observed that the N2/O2 separation is energetically driven and a high selectivity of O2 over N2 can be obtained at low temperatures. However, with the empirical potential both the energetic and entropic contributions to selectivity were found to be close to unity. Similarly, by calculating single-component fluxes and ideal selectivities at 300 K and finite pressures it is found that the ab initio potential better explains the large O2/N2 selectivities of similarly sized molecules that have been observed experimentally. An interesting reversal in ideal selectivity is observed by adjusting the pressure at the two ends of the membrane. As a consequence, we predict that a highly selective kinetic separation in favor of either nitrogen or oxygen could be obtained with the same membrane depending on the operating conditions.

Journal Article↗
PubMed2005

Hybrid approach for ab initio molecular dynamics simulation combining energy density analysis and short-time Fourier transform: energy transfer spectrogram.

We propose a new analysis technique for specifying molecular vibrational modes related with intramolecular and/or intermolecular energy transfer in ab initio molecular dynamics simulation of chemical reaction. The technique combines the short-time Fourier transform method with energy density analysis, which partitions the quantum chemical potential energy in the system into atomic contributions. The image obtained by the combined scheme, termed an energy transfer spectrogram (ETS), enables us to understand the dynamics of energy transfer by time-frequency representation. The time change of the local energy is quite important in chemical reactions. In order to assess the performance of the ETS, its application to the collision reaction between two carbon dioxide molecules is shown.

Journal Article↗
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↗
PubMed2025

Molecular dynamics simulations reveal subtle consequences of H3K9 and H3K27 tri-methylation on chromatin constituents.

Epigenetic modifications of histone tails are key mechanisms of genome regulation. In particular, tri-methylation of lysines (K) 9 and K27 of the histone H3 tail is important for genome silencing. In this work, we explore, using all-atom molecular dynamics simulations, the effect of these two epigenetic marks on the structure and interactions of the H3 tail in several contexts: isolated tails, nucleosomes, chromatosomes, and stacked nucleosomes. Overall, we find that although the isolated tails do not show significant conformational changes upon methylation, a more flexible and extended H3 tail compared to the native tail results in the nucleosome systems, with K9 methylation effects more pronounced. This change could facilitate the interaction of the tail with protein readers like heterochromatin protein 1 or Polycomb group. We also observe that both methylations increase the interactions of the H3 tail with the linker DNA in the context of the chromatosome, producing a chromatosome with tighter linker DNA, which could favor chromatin compaction. For stacked nucleosomes mimicking i±2 zigzag interactions, methylation of either K9 or K27 reduces the interactions of one of the H3 tails with its parental nucleosome and increases its interactions with the nonparental nucleosome, which could also help compact the chromatin fiber. In the three nucleosome-containing systems, we observe an asymmetry between the two tails, especially in the chromatosome, where one tail extends to interact with the linker DNA. This asymmetry modulates the effect that methylation has on each tail. Thus, overall, methylations of K9 and K27 have a subtle but notable impact on the H3 tail structure and its interactions within the chromatin fiber. These results help explain how this epigenetic modification compacts chromatin fibers and promotes longer-range interactions; these changes also guide how to approximate these effects in coarse-grained chromatin models.

Histones↗