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At least 1,135 records · Page 63Linked to original sources
PubMed1999

Constructing the suitable initial configuration of the membrane-protein system in molecular dynamics simulations.

A method for constructing the suitable initial configuration of the membrane-protein system for molecular dynamics (MD) simulations is presented. This method could provide some hydrated initial configurations and help us to determine the best surface area of the system by contracting the surface area and comparing the optimized lowest energy of the system by energy minimization. The gramicidin A (GA) channel in;the fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer was used as our model. Three configurations with different surface areas were selected and applied for one 400 ps and two 300 ps MD simulations at constant pressure and temperature. All simulations were fairly stable without any constraints. Through analysis of the MD trajectories we found that the system with the best surface area was more stable than the other two systems, whose sizes were changed in the simulations. Further analysis of the bilayer normal length and the order parameters of the lipid alkyl tails indicates that the system with the best surface area shows some characteristics of the L(alpha) phase, while both the smaller and the larger size systems have distinct deviations from the L(alpha) phase that we expect. This illustrates that the correct surface area and the suitable initial configuration have an important influence on the phase of the membrane in the MD simulation. In addition, by comparing the root mean square differences of GA relative to the initial structure and interaction energy between different components of the system for all three systems, we find that the state of the DMPC bilayer has exerted a significant influence on the structure of GA. All these results demonstrate the validity of our method for constructing the initial configuration of the membrane-protein system for MD simulations.

Carbon↗
PubMed1994

Local elevation: a method for improving the searching properties of molecular dynamics simulation.

The concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system.

Algorithms↗
PubMed2005

Understanding diffusion in confined systems: methane in a ZK4 molecular sieve. A molecular dynamics simulation study.

The equilibrium probability distribution of N methane molecules adsorbed in the interior of n alpha cages of the ZK4 zeolite, the all-silica analogue of zeolite A, is modeled by a modified hypergeometric distribution where the effects of mutual exclusion between particles are extracted from long molecular dynamics simulations. The trajectories are then analyzed in terms of time-correlation functions for the fluctuations in the occupation number of the alpha cages. The analysis digs out the correlations induced by the spatial distribution of the adsorbed molecules coupled with a migration mechanism where a molecule can pass from one alpha cage to another, one-by-one. These correlations lead to cooperative motion, which manifests itself as a nonexponential decay of the correlators. Our results suggest ways of developing improved lattice approaches that may be useful for studying diffusion in much larger systems and for a much longer observation time.

Journal Article↗
PubMed2005

Molecular dynamics simulation study of the role of evenly spaced poly(ethylene oxide) tethers on the aggregation of C60 fullerenes in water.

The aggregation behavior of C60 fullerenes and C60 fullerenes with six symmetrically tethered poly(ethylene oxide) oligomers [(PEO)-6-C60] in aqueous solutions has been studied using implicit solvent molecular dynamics simulations. Our simulations reveal that while the attraction between two (PEO)-6-C60 fullerenes in aqueous solution is stronger and longer range than that between two bare C60 fullerenes, the (PEO)-6-C60 fullerenes do not phase-separate in water but rather aggregate in chain-like clusters at concentrations where unmodified fullerenes completely phase-separate.

Letter↗
PubMed2002

Nonequilibrium molecular dynamics simulation of shear-induced alignment of amphiphilic model systems.

We study the shear-induced alignment transition from transverse to the shear plane to parallel and perpendicular in a lamellar or smectics system. A recently proposed simple continuum model for amphiphiles is studied by large-scale nonequilibrium molecular dynamics simulation. We find a shear-rate dependence of the alignment transition under shear flow, parallel at low and perpendicular alignment at high shear rates. To identify the alignment and degree of order of these shear-induced orientations by scattering, a 3D analysis of the scattering data is needed.

Journal Article↗
PubMed2003

Glass transition in an off-lattice protein model studied by molecular dynamics simulations.

In this paper we report the results of a numerical investigation of the glass transition phenomenon in a minimalist protein model. The inherent structure theory of Stillinger and Weber was applied to an off-lattice protein model with a native state beta-sheet motif. By using molecular dynamics simulations and the steepest descent method, sets of local potential energy minima were generated for the model over a range of temperatures. The mean potential energy of the inherent structures allowed to make rough estimates of the glass-transition temperature T(K). More accurately T(K) was computed by direct evaluations of the total and vibrational entropies. It is found that for the present model the thermodynamic ratio of the folding and glass-transition temperatures is 1.7 which is in good agreement with experimental observations.

Journal Article↗
PubMed2006

Molecular dynamics simulation of the human adenosine A3 receptor: agonist induced conformational changes of Trp243.

The adenosine A(3) receptor together with rhodopsin belongs to Class A of the G-protein coupled receptors. As the crystal structure of bovine rhodopsin represents the dark (inactive) state of the receptor, the details of GPCR activation are still unknown. In this molecular dynamics study we investigate how the homology model of the human adenosine A(3) receptor responds to ligand exposure. To this end we placed the homology model in a POPC membrane model. After equilibrating for 13 ns an agonist (Cl-IB-MECA) and an inverse agonist (PSB-10) were placed inside the putative binding pocket. In the following 10 ns molecular dynamics simulation we observed a different behaviour of the side-chain torsions of Trp243(6.48), depending on the presence or absence of the agonist or inverse agonist. This conformational change of Trp243 correlates with the assumed influence of ligands on receptor activation. Other predicted conformational changes of the receptor could not be observed yet. So Trp243 may represent the first switch in receptor activation.

Adenosine A3 Receptor Agonists↗
PubMed2005

High-temperature unfolding of a trp-cage mini-protein: a molecular dynamics simulation study.

BACKGROUND: Trp cage is a recently-constructed fast-folding miniprotein. It consists of a short helix, a 3,10 helix and a C-terminal poly-proline that packs against a Trp in the alpha helix. It is known to fold within 4 ns. RESULTS: High-temperature unfolding molecular dynamics simulations of the Trp cage miniprotein have been carried out in explicit water using the OPLS-AA force-field incorporated in the program GROMACS. The radius of gyration (Rg) and Root Mean Square Deviation (RMSD) have been used as order parameters to follow the unfolding process. Distributions of Rg were used to identify ensembles. CONCLUSION: Three ensembles could be identified. While the native-state ensemble shows an Rg distribution that is slightly skewed, the second ensemble, which is presumably the Transition State Ensemble (TSE), shows an excellent fit. The denatured ensemble shows large fluctuations, but a Gaussian curve could be fitted. This means that the unfolding process is two-state. Representative structures from each of these ensembles are presented here.

Computer Simulation↗
PubMed1995

The conformational flexibility of 5,6,7,8-tetrahydrobiopterin and 5,6,7,8-tetrahydroneopterin: a molecular dynamical simulation.

5,6,7,8-Tetrahydrobiopterin is an essential cofactor of diverse enzymes. Of the eight possible stereoisomers, only the 6R,1'R,2'S-configuration is biologically active. Other stereoisomers, as well as other reduced pterins such as, e.g. 5,6,7,8-tetrahydroneopterin, fail to exhibit significant cofactor activity. Different theoretical models (molecular mechanics, semi-empirical quantum chemical calculations) investigating the stereostructure of tetrahydrobiopterin have yielded diverging answers. It has been claimed on the basis of semi-empirical quantum chemical calculations that conformational properties, and thus particular features in overall shape, might be responsible for the unique biological properties of natural tetrahydrobiopterin in contrast, e.g. to 6R,1'S,2'R-5,6,7,8-tetrahydroneopterin. Molecular dynamical simulations of both molecules at realistic temperatures demonstrate, however, that they possess sufficient conformational flexibility as to render questionable any biological significance of mere conformational properties.

Biopterins↗
PubMed2000

New insights into the structure of abasic DNA from molecular dynamics simulations.

Abasic (AP) sites constitute a common form of DNA damage, arising from the spontaneous or enzymatic breakage of the N-glycosyl bond and the loss of a nucleotide base. To examine the effects of such damage on DNA structure, especially in the vicinity of the abasic sugar, four 1.5 ns molecular dynamics simulations of double-helical DNA dodecamers with and without a single abasic (tetrahydrofuran, X) lesion in a 5'-d(CXT) context have been performed and analyzed. The results indicate that the abasic site does not maintain a hole or gap in the DNA, but instead perturbs the canonical structure and induces additional flexibility close to the abasic site. In the apurinic simulations (i.e., when a pyrimidine is opposite the AP site), the abasic sugar flipped in and out of the minor groove, and the gap was water filled, except during the occurrence of a novel non-Watson-Crick C-T base pair across the abasic site. The apyrimidinic gap was not penetrated by water until the abasic sugar flipped out and remained extrahelical. Both AP helices showed kinks of 20-30 degrees at the abasic site. The Watson-Crick hydrogen bonds are more transient throughout the DNA double helices containing an abasic site. The abasic sugar displayed an unusually broad range of sugar puckers centered around the northern pucker. The increased motion of the bases and backbone near the abasic site appear to correlate with sequence-dependent helical stability. The data indicate that abasic DNA contorts more easily and in specific ways relative to unmodified DNA, an aspect likely to be important in abasic site recognition and hydrolysis.

Apurinic Acid↗
PubMedDate not supplied

Recognition of LXXLL by ligand binding domain of the Farnesoid X receptor in molecular dynamics simulation.

The Farnesoid X receptor (FXR) has recently become a potential therapeutical target. The recruitment of coactivator protein (specified by LXXLL sequence) is the initial step in transcriptional activation of nuclear receptors (NRs). In this paper, the process of recognition of the LXXLL motif by the ligand binding domain (LBD) of FXR is observed in a 25 ns molecular dynamics simulation. The hydrophobic and hydrogen bonding interactions between the LBD and the coactivator are fully analyzed. This observation provides justification for the 'on deck' model proposed by Nettles and Greene. At last, insight to the protein-polypeptide interactions and protein conformational changes are discussed.

Amino Acid Motifs↗
PubMed2005

Solid-state amorphization observed in the equilibrium-immiscible Cu-Re system by molecular dynamics simulations.

Assisted by ab initio calculations, an n-body Cu-Re potential is first constructed for the equilibrium-immiscible Cu-Re system under the second moment approximation of a tight-binding scheme. The proven realistic Cu-Re potential is then applied to perform the molecular dynamics simulations using the Cu-Re sandwich model. The simulations reveal that the interfacial free energy stored in the Cu/Re interfaces plays an important role in facilitating the spontaneous solid-state amorphization and that the amorphous interlayer grows in a layer-by-layer mode featuring an asymmetric behavior, i.e., the growth of the amorphous interlayer advances faster toward the Cu lattice than toward the Re direction. It is also found that with increasing the simulation time, the growth speed of the amorphous interlayer gradually slows down and eventually becomes zero when the interlayer reaches a thickness of about 1.47 nm. Interestingly, according to a recently proposed thermodynamic and kinetic model, the maximum thickness of the growing amorphous layer is limited by the available interfacial free energy and in the Cu-Re system, it is estimated to be around 1.35 nm, which is comparable with that observed from the simulations.

Journal Article↗
PubMed2005

Molecular dynamics simulations of the TEM-1 beta-lactamase complexed with cephalothin.

Herein, we present theoretical results aimed at elucidating the origin of the kinetic preference for penicillins over cephalosporins characteristic of the TEM/SHV subgroup of class A beta-lactamases. First, we study the conformational properties of cephalothin showing that the C2-down conformer of the dihydrothiazine ring is preferred over the C2-up one by approximately 2 kcal/mol in solution (0.4-1.4 kcal/mol in the gas phase). Second, the TEM-1 beta-lactamase complexed with cephalothin is investigated by carrying out a molecular dynamics simulation. The DeltaG(binding) energy is then estimated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and quantum chemical PBSA (QM-PBSA) computational schemes. The preferential binding of benzylpenicillin over cephalothin is reproduced by the different energetic calculations, which predict relative DeltaDeltaG(binding) energies ranging from 1.8 to 5.7 kcal/mol. The benzylpenicillin/cephalothin DeltaDeltaG(binding) energy is most likely due to the lower efficacy of cephalosporins than that of penicillins in order to simultaneously bind the "carboxylate pocket" and the "oxyanion hole" in the TEM-1 active site.

Anti-Bacterial Agents↗
PubMed2005

Conformational studies of two bradykinin antagonists by using two-dimensional NMR techniques and molecular dynamics simulations.

The solution conformations of two potent antagonists of bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9), [Aca(-1),DArg0,Hyp3,Thi5,DPhe7,(N-Bzl)Gly8]BK (1) and [Aaa(-1),DArg0,Hyp3,Thi5,(2-DNal)7,Thi8]BK (2), were studied by using 2D NMR spectroscopy in DMSO-d6 and molecular dynamics simulations. The NMR spectra of peptide 1 reveals the existence of at least two isomers arising from isomerization across the DPhe7-(N-Bzl)Gly8 peptide bond. The more populated isomer possesses the cis peptide bond at this position. The ratio of cis/trans isomers amounted to 7:3. With both antagonists, the NMR data indicate a beta-turn structure for the Hyp3-Gly4 residues. In addition, for peptide 2, position 2,3 is likely to be occupied by turn-like structures. The cis peptide bond between DPhe7 and (N-Bzl)Gly8 in analogue 1 suggests type VI beta-turn at position 7,8. The molecular dynamics runs were performed on both peptides in DMSO solution. The results indicate that the structure of peptide 1 is characterized by type VIb beta-turn comprising residues Ser6-Arg9 and the betaI or betaII-turn involving the Pro2-Thi5 fragment, whereas peptide 2 shows the tendency towards the formation of type I beta-turn at position 2,3. The structures of both antagonists are stabilized by a salt bridge between the guanidine moiety of Arg1 and the carboxyl group of Arg9. Moreover, the side chain of DArg0 is apart of the rest of molecule and is not involved in structural elements except for a few calculated structures.

Bradykinin↗
PubMed2004

Molecular dynamics simulation of a reverse micelle self assembly in supercritical CO2.

In this communication we report on molecular dynamics computer simulations of self-assembly of reverse micelles in supercritical carbon dioxide. The reverse micelles contain perfluoropolyether ammonium carboxylate surfactants and an aqueous core. We observed a quick self-assembly of these micelles over time periods of approximately 5 ns, irrespective of initial conditions. In most cases, the self-assembled perfluorinated reverse micelles have a nice spherical shape and properties consistent with experiments. When the fluorinated surfactant is replaced by its hydrogenated analogue, the assembled aggregate contains a region of direct contact between water and carbon dioxide, indicating that hydrogenated surfactant is not a good agent for creation of microemulsions in water/carbon dioxide mixtures.

Journal Article↗
PubMed2005

Probing the "annealing" mechanism of GroEL minichaperone using molecular dynamics simulations.

Although the intact chaperonin machinery is needed to rescue natural substrate proteins (SPs) under non-permissive conditions the "minichaperone" alone, containing only the isolated apical domain of GroEL, can assist folding of a certain class of proteins. To understand the annealing function of the minichaperone, we have carried out molecular dynamics simulations in the NPT ensemble totaling 300ns for four systems; namely, the isolated strongly binding peptide (SBP), the minichaperone, and the SBP and a weakly binding peptide (WBP) in complex with the minichaperone. The SBP, which is structureless in isolation, adopts a beta-hairpin conformation in complex with the minichaperone suggesting that favorable non-specific interactions of the SPs confined to helices H and I of the apical domains can induce local secondary structures. Comparison of the dynamical fluctuations of the apo and the liganded forms of the minichaperone shows that the stability (needed for SP capture) involves favorable hydrophobic interactions and hydrogen bond network formation between the SBP and WBP, and helices H and I. The release of the SP, which is required for the annealing action, involves water-mediated interactions of the charged residues at the ends of H and I helices. The simulation results are consistent with a transient binding release (TBR) model for the annealing action of the minichaperone. According to the TBR model, SP annealing occurs in two stages. In the first stage the SP is captured by the apical domain. This is followed by SP release (by thermal fluctuations) that places it in a different region of the energy landscape from which it can partition rapidly to the native state with probability Phi or be trapped in another misfolded state. The process of binding and release can result in enhancement of the native state yield. The TBR model suggests "that any cofactor that can repeatedly bind and release SPs can be effective in assisting protein folding." By comparing the structures of the non-chaperone alpha-casein (which has no sequence similarity with the apical domain) and the minichaperone and the hydrophobicity profiles we show that alpha-casein has a pair of helices that have similar sequence and structural profiles as H and I. Based on this comparison we identify residues that stabilize (destabilize) alpha-casein-protein complexes. This suggests that alpha-casein assists folding by the TBR mechanism.

Animals↗
PubMed1999

Androctonin, a novel antimicrobial peptide from scorpion Androctonus australis: solution structure and molecular dynamics simulations in the presence of a lipid monolayer.

Androctonin is a highly cationic antimicrobial peptide from scorpion exhibiting a broad spectrum of activities against bacteria and fungi. It contains 25 amino acids including four cysteine residues forming two disulfide bridges. We report here on the determination of its solution structure by conventional two-dimensional (2D) 1H-NMR spectroscopy and molecular modelling using distance geometry and molecular dynamics methods. The structure of androctonin involves a well-defined highly twisted anti-parallel beta-sheet with strands connected by a more variable positively charged turn. A comparison with the structure of tachyplesin I (horseshoe crab) reveals that the amphiphilic character of the protein surface of this homologous peptide is not observed in androctonin. We have undertaken a 200-ps molecular dynamics simulation study on a system including one androctonin molecule and a monolayer of DMPG (1,2-dimyristoylphosphatidylglycerol) lipids. On the basis of this simulation, the first steps of the membrane permeabilization process are discussed.

Amino Acid Sequence↗
PubMed1991

Molecular dynamics simulation of the renin inhibitor H142 in water.

H142 is a synthetic decapeptide designed to inhibit renin, an enzyme acting in the regulation of blood pressure. The inhibiting effect of H142 is caused by a reduction of a -Leu-Val-peptide bond (i. e. C(= O)-NH----CH2-NH). The conformational and dynamical properties of H142 and its unreduced counterpart (H142n) was modelled by means of molecular dynamics simulations. Water was either included explicitly in the simulations or as a dielectric continuum. When water molecules surround the peptides, they remain in a more or less extended conformation through the simulation. If water is replaced by a dielectric continuum, the peptides undergo a conformational change from an extended to a folded state. It is not clear whether this difference is a consequence of a too short simulation time for the water simulations, a force-field artifact promoting extended conformations, or if the extended conformation represents the true conformational state of the peptide. A number of dynamic properties were evaluated as well, such as overall rotation, translational diffusion, side-chain dynamics and hydrogen bonding.

Amino Acid Sequence↗