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Results for “Molecular Dynamic simulation”

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At least 541 records · Page 30Linked to original sources
PubMed1997

Molecular dynamics simulation in solvent of the estrogen receptor protein DNA binding domain in complex with a non-consensus estrogen response element DNA sequence.

We investigated protein/DNA interactions, using molecular dynamics simulations computed between a 10 Angstom water layer model of the estrogen receptor (ER) protein DNA binding domain (DBD) amino acids and DNA of a non-consensus estrogen response element (ERE) consisting of 29 nucleotide base pairs. This ERE nucleotide sequence occurs naturally upstream of the Xenopus laevis Vitelligenin A1 gene. The ER DBD is encoded by three exons. Namely, exons 2 and 3 which encode the two zinc binding motifs and a sequence of exon 4 which encodes a predicted alpha helix. We generated a computer model of the ER DBD using atomic coordinates derived from the average of 30 nuclear magnetic resonance (NMR) spectroscopy coordinate sets. Amino acids on the carboxyl end of the ER DBD were disordered in both X-ray crystallography and NMR determinations and no coordinates were reported. This disordered region includes 10 amino acids of a predicted alpha helix encoded in exon 4 at the exon 3/4 splice junction. These amino acids are known to be important in DNA binding and are also believed to function as a nuclear translocation signal sequence for the ER protein. We generated a computer model of the predicted alpha helix consisting of the 10 amino acids encoded in exon 4 and attached this helix to the carboxyl end of the ER DBD at the exon 3/4 splice junction site. We docked the ER DBD model within the DNA major groove halfsites of the 29 base pair non-consensus ERE and flanking nucleotides. We constructed a solvated model with the ER DBD/ERE complex surrounded by a ten Angstrom water layer and conducted molecular dynamics simulations. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Amino acids of the ER DBD DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon-anticodon nucleotide base and backbone sites within the ERE DNA right major groove halfsite. Amino acids of the ER DBD exon 4 encoded predicted alpha helix formed direct and water mediated H-bonds with base and backbone sites of their cognate codon-anticodon nucleotides within the minor grooves flanking the ERE DNA major groove halfsites. These interactions together induced bending of the DNA into the protein.

Animals↗
PubMed1993

Molecular dynamics simulation of a phospholipase A2-substrate complex.

We have used knowledge of the three-dimensional structure of phospholipids and phospholipases A2 together with biochemical data, computer graphics modelling and a 48 ps molecular dynamics simulation to predict the structure of a phospholipase A2-substrate complex. There is remarkable similarity between this predicted structure of enzyme-substrate complex and the structure that can be deduced from the observed enzyme-inhibitor complex. Molecular dynamics simulation highlights the importance of the calcium-ion in substrate binding and the persistence of the His-48 to water-hydrogen bond is compatible with the proposed role of this water molecule as the nucleophile in catalysis.

Animals↗
PubMed2003

Molecular dynamics simulations of a K+ channel blocker: Tc1 toxin from Tityus cambridgei.

Toxins that block voltage-gated potassium (Kv) channels provide a possible template for improved homology models of the Kv pore. In assessing the interactions of Kv channels and their toxins it is important to determine the dynamic flexibility of the toxins. Multiple 10 ns duration molecular dynamics simulations combined with essential dynamics analysis have been used to explore the flexibility of four different Kv channel-blocking toxins. Three toxins (Tc1, AgTx and ChTx) share a common fold. They also share a common pattern of conformational dynamics, as revealed by essential dynamics analysis of the simulation results. This suggests that some aspects of dynamic behaviour are conserved across a single protein fold class. In each of these three toxins, the residue exhibiting minimum flexibility corresponds to a conserved lysine residue that is suggested to interact with the filter domain of the channel. Thus, comparative simulations reveal functionally important conservation of molecular dynamics as well as protein fold across a family of related toxins.

Animals↗
PubMed2007

Cooperative folding mechanism of a beta-hairpin peptide studied by a multicanonical replica-exchange molecular dynamics simulation.

G-peptide is a 16-residue peptide of the C-terminal end of streptococcal protein G B1 domain, which is known to fold into a specific beta-hairpin within 6 micros. Here, we study molecular mechanism on the stability and folding of G-peptide by performing a multicanonical replica-exchange (MUCAREM) molecular dynamics simulation with explicit solvent. Unlike the preceding simulations of the same peptide, the simulation was started from an unfolded conformation without any experimental information on the native conformation. In the 278-ns trajectory, we observed three independent folding events. Thus MUCAREM can be estimated to accelerate the folding reaction more than 60 times than the conventional molecular dynamics simulations. The free-energy landscape of the peptide at room temperature shows that there are three essential subevents in the folding pathway to construct the native-like beta-hairpin conformation: (i) a hydrophobic collapse of the peptide occurs with the side-chain contacts between Tyr45 and Phe52, (ii) then, the native-like turn is formed accompanying with the hydrogen-bonded network around the turn region, and (iii) finally, the rest of the backbone hydrogen bonds are formed. A number of stable native hydrogen bonds are formed cooperatively during the second stage, suggesting the importance of the formation of the specific turn structure. This is also supported by the accumulation of the nonnative conformations only with the hydrophobic cluster around Tyr45 and Phe52. These simulation results are consistent with high phi-values of the turn region observed by experiment.

Aspartic Acid↗
PubMed2005

Conformational dynamics of M2 helices in KirBac channels: helix flexibility in relation to gating via molecular dynamics simulations.

KirBac1.1 and 3.1 are bacterial homologues of mammalian inward rectifier K channels. We have performed extended molecular dynamics simulations (five simulations, each of >20 ns duration) of the transmembrane domain of KirBac in two membrane environments, a palmitoyl oleoyl phosphatidylcholine bilayer and an octane slab. Analysis of these simulations has focused on the conformational dynamics of the pore-lining M2 helices, which form the cytoplasmic hydrophobic gate of the channel. Principal components analysis reveals bending of M2, with a molecular hinge at the conserved glycine (Gly134 in KirBac1.1, Gly120 in KirBac3.1). More detailed analysis reveals a dimer-of-dimers type motion. The first two eigenvectors describing the motions of M2 correspond to helix kink and swivel motions. The conformational flexibility of M2 seen in these simulations correlates with differences in M2 conformation between that seen in the X-ray structures of closed channels (KcsA and KirBac) in which the helix is undistorted, and in open channels (e.g. MthK) in which the M2 helix is kinked. Thus, the simulations, albeit on a time scale substantially shorter than that required for channel gating, suggest a gating model in which the intrinsic flexibility of M2 about a molecular hinge is coupled to conformational transitions of an intracellular 'gatekeeper' domain, the latter changing conformation in response to ligand binding.

Animals↗
PubMed2005

Large-scale molecular-dynamics simulation of nanoscale hydrophobic interaction and nanobubble formation.

We performed large-scale molecular-dynamics simulation of nanoscale hydrophobic interaction manifested by the formation of nanobubble between nanometer-sized hydrophobic clusters at constrained equilibrium. Particular attention is placed on the tendency of formation and stability of nanobubbles in between model nanoassemblies which are composed of hydrophobic clusters (or patches) embedded in a hydrophilic substrate. On the basis of physical behavior of nanobubble formation, we observed a change from short-range molecular hydrophobic interaction to midrange nanoscopic interaction when the length scale of hydrophobe approaches to about 1 nm. We investigated the behavior of nanobubble formation with several different patterns of nonpolar-site distribution on the nanoassemblies but always keeping a constant ratio of nonpolar to polar monomer sites. Dynamical properties of confined water molecules in between nanoassemblies are also calculated.

Chemistry, Physical↗
PubMed2006

Amyloid fibril structure modeling using protein threading and molecular dynamics simulations.

The elucidation of the structure of amyloid fibrils is an important step toward understanding the mechanism of amyloid formation and developing new reagents that could inhibit fibril formation. Here we describe an approach to modeling amyloid fibril structures using computational techniques, including protein threading and molecular dynamics simulations. Specifically, we introduce these methods using Abeta amyloid fibril modeling as an example. First, the amyloid protein sequence is threaded against a set of structural templates. Structural models are generated on the basis of threading alignments and are then subjected to molecular dynamic simulations to assess the stabilities of the model.

Amyloid beta-Peptides↗
PubMed2026

Molecular docking, molecular dynamics simulation, and enzyme inhibitory studies of vitamin K family members on aldose reductase.

Aldose reductase (AR) is a key enzyme in the polyol pathway and plays a major role in the progression of secondary complications of diabetes. Despite extensive efforts to develop natural and synthetic aldose reductase inhibitors (ARIs), most candidates have shown limited clinical efficacy, highlighting the need for more potent and selective inhibitors. In this study, we have systematically evaluated the inhibitory potential of vitamin K family members (vitamin K1, vitamin K2, and vitamin K3) using molecular docking, protein-ligand interaction analysis, molecular dynamics simulations, and enzyme kinetics. Docking analysis predicted that vitamin K2 has the highest binding affinity for AR. Subsequent molecular dynamics simulations revealed that both vitamin K1 and vitamin K2 formed stable complexes with the protein, exhibiting comparable RMSD (∼0.5 Å difference), similar RMSF profiles, and reduced radius of gyration, indicating compact and stable binding. Interaction analysis demonstrated that ligand binding is predominantly driven by hydrophobic interactions, with vitamin K2 forming a higher number of hydrophobic contacts, while vitamin K1 exhibited slightly more hydrogen bonding. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) results further supports stronger binding of vitamin K2 (-56 kcal/mol) compared to vitaminK1 (-51 kcal/mol). Consistent with these findings, enzyme kinetics showed a slightly lower Ki value for vitamin K2 than vitamin K1. In contrast, vitamin K3 failed to maintain stable binding and moved out of the active site during simulation. Overall, the study highlights that hydrophobic interaction-driven stabilization plays a key role in ligand binding, and identifies vitamin K1 and vitamin K2 as promising inhibitors against AR, with vitamin K2 exhibiting more favourable hydrophobic interactions and binding stability.

Aldose Reductase↗
PubMed2002

Molecular dynamics simulation of site-directed spin labeling: experimental validation in muscle fibers.

We have developed a computational molecular dynamics technique to simulate the motions of spin labels bound to the regulatory domain of scallop myosin. These calculations were then directly compared with site-directed spin labeling experimental results obtained by preparing seven single-cysteine mutants of the smooth muscle (chicken gizzard) myosin regulatory light chain and performing electron paramagnetic resonance experiments on these spin-labeled regulatory light chains in functional scallop muscle fibers. We determined molecular dynamics simulation conditions necessary for obtaining a convergent orientational trajectory of the spin label, and from these trajectories we then calculated correlation times, orientational distributions, and order parameters. Simulated order parameters closely match those determined experimentally, validating our molecular dynamics modeling technique, and demonstrating our ability to predict preferred sites for labeling by computer simulation. In several cases, more than one rotational mode was observed within the 14-ns trajectory, suggesting that the spin label samples several local energy minima. This study uses molecular dynamics simulations of an experimental system to explore and enhance the site-directed spin labeling technique.

Animals↗
PubMed2006

Molecular-dynamics simulations and master-equation description of a chemical wave front: effects of density and size of reaction zone on propagation speed.

We compare the master-equation description and molecular-dynamics simulations of a chemical wave front. We find that the front propagation speed depends on the number of particles in the reaction zone. For the master equation the dependence follows the well-known logarithmic prediction obtained when introducing a cutoff into the macroscopic reaction-diffusion equation. The molecular-dynamics simulations reveal that the logarithmic law is compromised for dense fluids.

Journal Article↗
PubMed2006

Molecular dynamics simulations of sarcin-ricin rRNA motif.

Explicit solvent molecular dynamics (MD) simulations were carried out for sarcin-ricin domain (SRD) motifs from 23S (Escherichia coli) and 28S (rat) rRNAs. The SRD motif consists of GAGA tetraloop, G-bulged cross-strand A-stack, flexible region and duplex part. Detailed analysis of the overall dynamics, base pairing, hydration, cation binding and other SRD features is presented. The SRD is surprisingly static in multiple 25 ns long simulations and lacks any non-local motions, with root mean square deviation (r.m.s.d.) values between averaged MD and high-resolution X-ray structures of 1-1.4 A. Modest dynamics is observed in the tetraloop, namely, rotation of adenine in its apex and subtle reversible shift of the tetraloop with respect to the adjacent base pair. The deformed flexible region in low-resolution rat X-ray structure is repaired by simulations. The simulations reveal few backbone flips, which do not affect positions of bases and do not indicate a force field imbalance. Non-Watson-Crick base pairs are rigid and mediated by long-residency water molecules while there are several modest cation-binding sites around SRD. In summary, SRD is an unusually stiff rRNA building block. Its intrinsic structural and dynamical signatures seen in simulations are strikingly distinct from other rRNA motifs such as Loop E and Kink-turns.

Animals↗
PubMed2005

Properties of inhibitors of methane hydrate formation via molecular dynamics simulations.

Within the framework of a proposed two-step mechanism for hydrate inhibition, the energy of binding of four inhibitor molecules (PEO, PVP, PVCap, and VIMA) to a hydrate surface is estimated with molecular dynamic simulations. One key feature of this proposed mechanism is that the binding of an inhibitor molecule to the surface of an ensuing hydrate crystal disrupts growth and therein crystallization. It is found through the molecular dynamic simulations that inhibitor molecules that experimentally exhibit better inhibition strength also have higher free energies of binding, an indirect confirmation of our proposed mechanism. Inhibitors increasing in effectiveness, PEO < PVP < PVCap < VIMA, have increasingly negative (exothermic) binding energies of -0.2 < -20.6 < -37.5 < -45.8 kcal/mol and binding free energies of increasing favorability (+0.4 approximately = +0.5 < -9.4 < -15.1 kcal/mol). Furthermore, the effect of an inhibitor molecule on the local liquid water structure under hydrate-forming conditions was examined and correlated to the experimental effectiveness of the inhibitors. Two molecular characteristics that lead to strongly binding inhibitors were found: (1) a charge distribution on the edge of the inhibitor that mimics the charge separation in the water molecules on the surface of the hydrate and (2) the congruence of the size of the inhibitor with respect to the available space at the hydrate-surface binding site. Equipped with this molecular-level understanding of the process of hydrate inhibition via low-dosage kinetic hydrate inhibitors we can design new, more effective inhibitor molecules.

Journal Article↗
PubMed1994

Molecular dynamics simulations of an enzyme surrounded by vacuum, water, or a hydrophobic solvent.

We report on molecular dynamics simulations of a medium-sized protein, a lipase from Rhizomucor miehei, in vacuum, in water, and in a nonpolar solvent, methyl hexanoate. Depending on force field and solvent, the molecular dynamics structures obtained as averages over 150 ps had root-mean-square deviations in the range of 1.9 to 3.6 A from the crystal structure. The largest differences between the structures were in hydrogen bonding and exposed surface areas of the protein. The surface area increased in both solvents and became smaller in vacuum. The change of surface exposure varied greatly between different residues and occurred in accordance with the hydrophobicity of the residue and the nature of the solvent. The fluctuations of the atoms were largest in the external loops and agreed well with crystallographic temperature factors. Root-mean-square fluctuations were significantly smaller in the nonpolar solvents than they were in water, which is in accordance with the notion that proteins become more rigid in nonpolar solvents. In methyl hexanoate a partial opening of the lid covering the active site occurred, letting a methyl hexanoate molecule approach the active site.

Computer Simulation↗
PubMed1997

Transmembrane helix structure, dynamics, and interactions: multi-nanosecond molecular dynamics simulations.

To probe the fundamentals of membrane/protein interactions, all-atom multi-nanosecond molecular dynamics simulations were conducted on a single transmembrane poly(32)alanine helix in a fully solvated dimyristoyphosphatidylcholine (DMPC) bilayer. The central 12 residues, which interact only with the lipid hydrocarbon chains, maintained a very stable helical structure. Helical regions extended beyond these central 12 residues, but interactions with the lipid fatty-acyl ester linkages, the lipid headgroups, and water molecules made the helix less stable in this region. The C and N termini, exposed largely to water, existed as random coils. As a whole, the helix tilted substantially, from perpendicular to the bilayer plane (0 degree) to a 30 degrees tilt. The helix experienced a bend at its middle, and the two halves of the helix at times assumed substantially different tilts. Frequent hydrogen bonding, of up to 0.7 ns in duration, occurred between peptide and lipid molecules. This resulted in correlated translational diffusion between the helix and a few lipid molecules. Because of the large variation in lipid conformation, the lipid environment of the peptide was not well defined in terms of "annular" lipids and on average consisted of 18 lipid molecules. When compared with a "neat" bilayer without peptide, no significant difference was seen in the bilayer thickness, lipid conformations or diffusion, or headgroup orientation. However, the lipid hydrocarbon chain order parameters showed a significant decrease in order, especially in those methylene groups closest to the headgroup.

Computer Simulation↗
PubMed1999

A molecular dynamics simulation of the flavin mononucleotide-RNA aptamer complex.

We report on an unrestrained molecular dynamics simulation of the flavin mononucleotide (FMN)-RNA aptamer. The simulated average structure maintains both cross-strand and intermolecular FMN-RNA nuclear Overhauser effects from the nmr experiments and has all qualitative features of the nmr structure including the G10-U12-A25 base triple and the A13-G24, A8-G28, and G9-G27 mismatches. However, the relative orientation of the hairpin loop to the remaining part of the molecule differs from the nmr structure. The simulation predicts that the flexible phosphoglycerol part of FMN moves toward G27 and forms hydrogen bonds. There are structurally long-lived water molecules in the FMN binding pocket forming hydrogen bonds within FMN and between FMN and RNA. In addition, long-lived water is found bridging primarily RNA backbone atoms. A general feature of the environment of long-lived "structural" water is at least two and in most cases three or four potential acceptor atoms. The 2'-OH group of RNA usually acts as an acceptor in interactions with the solvent. There are almost no intrastrand O2'H(n) vertical ...O4'(n + 1) hydrogen bonds within the RNA backbone. In the standard case the preferred orientation of the 2'-OH hydrogen atoms is approximately toward O3' of the same nucleotide. However, a relatively large number of conformations with the backbone torsional angle gamma in the trans orientation is found. A survey of all experimental RNA x-ray structures shows that this backbone conformation occurs but is less frequent than found in the simulation. Experimental nmr RNA aptamer structures have a higher fraction of this conformation as compared to the x-ray structures. The backbone conformation of nucleotide n + 1 with the torsional angle gamma in the trans orientation leads to a relatively short distance between 2'-OH(n) and O5'(n + 1), enabling hydrogen-bond formation. In this case the preferred orientation of the 2'-OH hydrogen atom is approximately toward O5'(n + 1). We find two relatively short and dynamically stable types of backbone-backbone next-neighbor contacts, namely C2'(H)(n) vertical ...O4'(n + 1) and C5'(H)(n + 1) vertical ...O2'(n). These interactions may affect both backbone rigidity and thermodynamic stability of RNA helical structures.

Computer Simulation↗
PubMed2006

Molecular dynamics simulation of monoalkyl glycoside micelles in aqueous solution: influence of carbohydrate headgroup stereochemistry.

Comparative molecular dynamics simulations of n-octyl-beta-D-galactopyranoside (beta-C8Gal) and n-octyl-beta-D-glucopyranoside (beta-C8Glc) micelles in aqueous solution have been performed to explore the influence of carbohydrate stereochemistry on glycolipid properties at the atomic level. In particular, we explore the hypothesis that differences in T(m) and T(c) for beta-C8Gal and beta-C8Glc in lyotropic systems arise from a more extensive hydrogen bonding network between beta-C8Gal headgroups relative to beta-C8Glc, due to the axial 4-OH group in beta-C8Gal. Good agreement of the 13 ns micelle-water simulations with available experimental information is found. The micelles exhibit a similar shape, size, and degree of exposed alkyl chain surface area. We find net inter- and intra-headgroup hydrogen bonding is also similar for beta-C8Gal and beta-C8Glc, although n-octyl-beta-D-galactopyranoside micelles do exhibit a slightly greater degree of inter- and intra-headgroup hydrogen bonding. However, the main distinction in the calculated microscopic behavior of beta-C8Glc and beta-C8Gal micelles lies in solvent interactions, where beta-d-glucosyl headgroups are considerably more solvated (mainly at the equatorial O4 oxygen). These results agree with preceding theoretical and experimental studies of monosaccharides in aqueous solution. A number of long water residence times are found for solvent surrounding both micelle types, the largest of which are associated with surface protrusions involving headgroup clusters. Our simulations, therefore, predict differences in hydrogen bonding for the two headgroup stereochemistries, including a small difference in inter-headgroup interactions, which may contribute to the higher T(m) and T(c) values of beta-C8Gal surfactants relative to beta-C8Glc in lyotropic systems.

Carbohydrate Sequence↗
PubMed1999

Molecular dynamics simulation of alpha-melanocyte stimulating hormone in a water-membrane model interface.

The conformation of the tridecapeptide alpha-melanocyte stimulating hormone in the presence of a double water-membrane interface was studied by molecular dynamics simulation, using the computational package THOR. In this program the solvent is represented by a continuous medium with dielectric constant epsilon, and the interface between different media is simulated by a surface of discontinuity of the dielectric constant. The electrostatic image method was used to write down the terms, added to the force field, that describe the polarisation effects induced in the interface by the atomic charges. The program was further improved by the introduction of a second surface, parallel to the first one, to mimic the membrane. A conformational search using the software Prelude was employed to find an initial geometry for the peptide in water. The molecular dynamics simulation performed during 10 ns showed that the peptide structure is flexible in water, without stabilisation of any preferential conformation. In the presence of the model membrane, the peptide moved to the medium representing the interior of the membrane. Inside the low dielectric constant medium, the structure of the peptide showed a turn in the central sequence of amino acids and a packed conformation remained stabilised during more than 7.0 ns of simulation.

Amino Acid Sequence↗
PubMed2001

Molecular dynamics simulations of the mononuclear zinc-beta-lactamase from Bacillus cereus.

Herein, we report molecular dynamics simulations of the mononuclear form of the Bacillus cereuszinc-beta-lactamase. We studied two different configurations which differ in the presence of a zinc-bound hydroxide or a zinc-bound water and in the protonation state of the essential His210 residue. Contacts of the catalytically important residues (Asp90, His210, Cys168, etc.) with the zinc center are characterized by the MD analyses. The nature of the Zn-OH(2) --> His210 proton transfer pathway connecting the two configurations was studied by means of QM calculations on cluster models while the relative stability of the two configurations was estimated from QM/MM calculations in the enzyme. From these results, a theoretical model for the kinetically active form of the B. cereus metalloenzyme is proposed. Some mechanistic implications and the influence of mutating the Cys168 residue are also discussed.

Bacillus cereus↗