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At least 991 records · Page 55Linked to original sources
PubMed2001

Changes in a phospholipid bilayer induced by the hydrolysis of a phospholipase A2 enzyme: a molecular dynamics simulation study.

Phospholipase A2 (PLA2) enzymes are important in numerous physiological processes. Their function at lipid-water interfaces is also used as a biophysical model for protein-membrane interactions. These enzymes catalyze the hydrolysis of the sn-2 bonds of various phospholipids and the hydrolysis products are known to increase the activity of the enzymes. Here, we have applied molecular dynamics (MD) simulations to study the membrane properties in three compositionally different systems that relate to PLA2 enzyme action. One-nanosecond simulations were performed for a 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) bilayer and for two of its PLA2-hydrolyzed versions, i.e., bilayers consisting of lysophospholipids and of either free charged linoleate or free uncharged linoleic acid molecules. The results revealed loosening of the structure in the hydrolyzed bilayer due to increased mobility of the molecules in the direction normal to the bilayer. This loss of integrity due to the hydrolysis products is in accord with observations that not only the presence of hydrolysis products, but also a variety of other perturbations of the membrane may activate PLA2. Additionally, changes were observed in other structural parameters and in the electrostatic potential across the membrane-water interface. These changes are discussed in relation to the simulation methodology and the experimental observations of PLA2-hydrolyzed membranes.

Biophysical Phenomena↗
PubMed1997

Effect of periodic box size on aqueous molecular dynamics simulation of a DNA dodecamer with particle-mesh Ewald method.

The particle-mesh Ewald (PME) method is considered to be both efficient and accurate for the evaluation of long-range electrostatic interactions in large macromolecular systems being studied by molecular dynamics simulations. This method assumes "infinite" periodic boundary conditions resembling the symmetry of a crystal environment. Can such a "solid-state" method accurately portray a macromolecular solute such as DNA in solution? To address this issue, we have performed three 1500-ps PME molecular dynamics (MD) simulations, each with a different box size, on the d(CGCGA6CG)-(CGT6CGCG) DNA dodecamer. The smallest box had the DNA solvated by a layer of water molecules of at least 5 A along each orthogonal direction. The intermediate size box and the largest box had the DNA solvated by a layer of water molecules of at least 10 A and 15 A, respectively, along each orthogonal direction. The intermediate size box in the present study is similar to the box size currently chosen by most workers in the field. Based on a comparison of RMSDs and curvature for this single DNA dodecamer sequence, the larger two box sizes do not appear to afford any extra benefit over the smallest box. The implications of this finding are briefly discussed.

Base Sequence↗
PubMed1998

Importance of explicit salt ions for protein stability in molecular dynamics simulation.

The accurate and efficient treatment of electrostatic interactions is one of the challenging problems of molecular dynamics simulation. Truncation procedures such as switching or shifting energies or forces lead to artifacts and significantly reduced accuracy. The particle mesh Ewald (PME) method is one approach to overcome these problems by providing a computationally efficient means of calculating all long-range electrostatic interactions in a periodic simulation box by use of fast Fourier transformation techniques. For the application of the PME method to the simulation of a protein with a net charge in aqueous solution, counterions are added to neutralize the system. The usual procedure is to add charge-balancing counterions close to charged residues to neutralize the protein surface. In the present article, we show that for MD simulation of a small protein of marginal stability, the YAP-WW domain, explicit modeling of 0.2 M ionic strength (in addition to the charge-balancing counterions) is necessary to maintain a stable protein structure. Without explicit ions throughout the periodic simulation box, the charge-balancing counterions on the protein surface diffuse away from the protein, resulting in destruction of the beta-sheet secondary structure of the WW domain.

Computer Simulation↗
PubMed1989

[Deoxyribonucleic acid sequence effects on molecular structure].

The deoxyribonucleic acid (DNA) duplex shows polymorphism depending on the base sequence and the environment. The base sequence dependent variations in conformational properties of the synthesized oligonucleotides are studied by X-ray analysis and several physico-chemical techniques. The possible structures in solution were proposed by molecular dynamics (MD) simulation. 1) The several oligonucleotides which include the adenine or adenine-thiamine tract, have unique conformational characteristics with the base sequence dependent property. The junction-model structure for DNA bending was proposed by the combined method of nuclear magnetic resonance (NMR) observations and MD calculation. 2) The two different hydrogen bonding schemes of inosine-adenine base-pairing, anti/anti and anti/syn forms, are adopted in B-DNA structure. The preference of these forms depends on the base sequence. The MD calculation could offer the models consistent with NMR evidence. 3) Oligonucleotides containing cyclonucleosides with a high-anti (intermediate between anti and syn) glycosidic conformation adopt left-handed double-helical structures. A suitable model of this left-handed duplex was proposed by calculation with energy minimization.

Adenine↗
PubMed2006

Local feature analysis: a statistical theory for reproducible essential dynamics of large macromolecules.

Multivariate statistical methods are widely used to extract functional collective motions from macromolecular molecular dynamics (MD) simulations. In principal component analysis (PCA), a covariance matrix of positional fluctuations is diagonalized to obtain orthogonal eigenvectors and corresponding eigenvalues. The first few eigenvectors usually correspond to collective modes that approximate the functional motions in the protein. However, PCA representations are globally coherent by definition and, for a large biomolecular system, do not converge on the time scales accessible to MD. Also, the forced orthogonalization of modes leads to complex dependencies that are not necessarily consistent with the symmetry of biological macromolecules and assemblies. Here, we describe for the first time the application of local feature analysis (LFA) to construct a topographic representation of functional dynamics in terms of local features. The LFA representations are low dimensional, and like PCA provide a reduced basis set for collective motions, but they are sparsely distributed and spatially localized. This yields a more reliable assignment of essential dynamics modes across different MD time windows. Also, the intrinsic dynamics of local domains is more extensively sampled than that of globally coherent PCA modes.

Bacteriophage T4↗
PubMed2003

A box-counting-based algorithm for computing Shannon entropy in molecular dynamics simulations.

A box-counting-based algorithm (SEBC) has been developed for the numerical computation of the Shannon entropy from samples of continuous functions. Its performance was tested by applying it to several samples of known continuous distribution functions. The results obtained with SEBC reproduced those obtained by analytical or numerical integration. SEBC was also employed for computing the Shannon entropies of the steric energy, Sh(E(S)), of several amino acids from their in vacuo NVE molecular dynamics simulations using the AMBER-4 force field. The results obtained correlate linearly with the experimental standard thermodynamic entropies of these compounds. This work points to the possibility of introducing straightforward and reliable calculations of thermodynamic entropies from empirical linear relationships with Sh(E(S)) obtained from MD simulations.

Journal Article↗
PubMed2006

A molecular dynamics simulation study of an aminoglycoside/A-site RNA complex: conformational and hydration patterns.

Aminoglycoside antibiotics interfere with the translation mechanism by binding to the tRNA decoding site of the 16S ribosomal RNA. Crystallographic structures of aminoglycosides bound to A-site systems clarified many static aspects of RNA-ligand interactions. To gain some insight on the dynamic aspects of recognition phenomena, we conducted molecular dynamics simulations of the aminoglycoside paromomycin bound to a eubacterial ribosomal decoding A-site oligonucleotide. Results from 25 ns of simulation time revealed that: (i) the neamine part of the antibiotic represents the main anchor for binding, (ii) additional sugar rings provide limited and fragile contacts, (iii) long-resident water molecules present at the drug/RNA interface are involved in the recognition phenomena. The combination of MD simulations together with systematic structural information offers striking insights into the molecular recognition processes underlying RNA/aminoglycoside binding. Important methodological considerations related to the use of medium resolution starting structures and associated sampling problems are thoroughly discussed.

Aminoglycosides↗
PubMed2006

Explicit solvent DRF INDOs/CIS computations of charge transfer state energetics in a pyrenyldeoxyuridine nucleoside model.

In this work we present calculated absorption and emission spectra in acetonitrile (MeCN) solution of N-acetyl-1-aminopyrene (PAAc, a spectroscopic model compound) and N-(1-pyrenyl)-1-methyluracil-5-carboxamide (PAU(Me), a computational model for 5-(N-carboxyl-1-aminopyrenyl)-2'-deoxyuridine (PAdU)). The computational method used--the discrete reaction field approach (DRF)--combines a quantum mechanical (QM) description of the solute (here DFT and INDOs/CIS, i.e., the INDO parametrization for spectroscopy) with a classical, molecular mechanics (MM) description of the solvent molecules. The latter are modeled with point charges representing the permanent charge distribution and polarizabilities to account for many-body interactions among the solute and other solvent molecules. Molecular dynamics is used to sample the degrees of freedom of the solution around several solute conformations each in two electronic excited states. This leads to a large number of solute/solvent configurations from which 800 are selected for each excited state and collected into a single ensemble by means of proper Boltzmann averaging. DRF INDOs/CIS applied to the selected solute/solvent configurations give simulated absorption and emission band spectra--each based on 15,200 calculated transitions--that compare well with experimental results. For example, the much broader absorption and emission bands in PAdU compared with PAAc are reproduced, and the simulated emission spectra of PAU(Me) agree well with broad (380-550 nm) charge transfer (CT) emission seen for PAdU in MeCN. The observed multiexponential fluorescence decay profiles for PAdU in different polar solvents are interpreted in terms of solute/solvent conformational heterogeneity here generated in the MD simulations for PAU(Me) in MeCN. Additionally, the simulations demonstrate the mixing of the forbidden Py*+/dU*- CT states with allowed pyrenyl 1(pi,pi*) states.

Journal Article↗
PubMed2006

Direct observation of salt effects on molecular interactions through explicit-solvent molecular dynamics simulations: differential effects on electrostatic and hydrophobic interactions and comparisons to Poisson-Boltzmann theory.

Proteins and other biomolecules function in cellular environments that contain significant concentrations of dissolved salts and even simple salts such as NaCl can significantly affect both the kinetics and thermodynamics of macromolecular interactions. As one approach to directly observing the effects of salt on molecular associations, explicit-solvent molecular dynamics (MD) simulations have been used here to model the association of pairs of the amino acid analogues acetate and methylammonium in aqueous NaCl solutions of concentrations 0, 0.1, 0.3, 0.5, 1, and 2 M. By performing simulations of 500 ns duration for each salt concentration properly converged estimates of the free energy of interaction of the two molecules have been obtained for all intermolecular separation distances and geometries. The resulting free energy surfaces are shown to give significant new insights into the way salt modulates interactions between molecules containing both charged and hydrophobic groups and are shown to provide valuable new benchmarks for testing the description of salt effects provided by the simpler but faster Poisson-Boltzmann method. In addition, the complex many-dimensional free energy surfaces are shown to be decomposable into a number of one-dimensional effective energy functions. This decomposition (a) allows an unambiguous view of the qualitative differences between the salt dependence of electrostatic and hydrophobic interactions, (b) gives a clear rationalization for why salt exerts different effects on protein-protein association and dissociation rates, and (c) produces simplified energy functions that can be readily used in much faster Brownian dynamics simulations.

Acetates↗
PubMed2003

Determination of the active site protonation state of beta-secretase from molecular dynamics simulation and docking experiment: implications for structure-based inhibitor design.

Memapsin 2 (BACE) is an aspartyl protease known as beta-secretase that acts on the production of the beta-amyloid peptide in the human brain, a key event in the pathogenesis of Alzheimer's disease. Although it is expected that the net charge of the catalytic Asp diad would be -1 as in other kinds of aspartyl proteases, the exact protonation states of Asp32 and Asp228 have not been known without ambiguity. Two independent molecular dynamics (MD) simulations of BACE in complex with the potent inhibitor OM99-2 are carried out to determine the preferred protonation state of the Asp diad in the context that is consistent with the previous X-ray crystal structure. The results show that a strong hydrogen bond between the inhibitor hydroxyl group and Asp228 can be maintained only when Asp32 is neutral and Asp228 is ionized. The preference of this protonation state is further supported from the energetic and structural features found in the docking experiment of a novel potent inhibitor with the BACE active site. Thus, both MD and docking studies suggest that the role of hydrogen bond acceptor for the hydroxyl and piperazine groups of the inhibitors should be played by Asp228 instead of Asp32. This may be a key piece of information for the structure-based design/discovery of new inhibitor drugs.

Amyloid Precursor Protein Secretases↗
PubMed1991

Molecular dynamics simulation of the aqueous solvation of sugars.

Recently, several molecular dynamics simulations of the aqueous solvation of carbohydrates have been reported. These studies represent the first theoretical picture available of the microscopic character of sugar solutions, and may provide explanations of the unusual and complex behavior of this class of molecules in solution. This paper will discuss two MD simulations of D-glucopyranose, including a free energy perturbation calculation of the anomeric free energy difference. Solvation was found to have little effect upon the mean conformational structure of the pyranoid rings, but the presence of solvent significantly affected the motions and orientations of the exocyclic groups. Adjacent functional groups of the sugar rings were found to mutually perturb one another's hydration, depending upon the local stereochemistry, which may prove to play a part in the observed anomeric preferences of the sugars. From a component analysis of the free energy of solvation of the two anomers of D-glucopyranose, it was found that a large solvation term favors the beta anomer, which is the form found to be preferred in aqueous solution.

Carbohydrates↗
PubMed2005

A multi-scale stochastic drug release model for polymer-coated targeted drug delivery systems.

A multi-scale mathematical model for drug release of oral targeted drug delivery systems was developed and applied to a commercially available delayed release tablet (Asacol) that delivers 5-aminosalicyclic acid (5-ASA) to the colon. Underlying physical and biochemical principles governing the involved processes (diffusion and dissolution) were employed to develop the mathematical description. Finite element formulation was used to numerically solve the model equations. Molecular dynamics (MD) simulations were used to predict macro-scale transport properties of the drug and the biologic fluid. The effect of pH variability in the gastrointestinal tract environment on the dissolution of the polymeric enteric coating was investigated using the Monte Carlo method. The direct coupling method employed (MD) predicted a sufficiently accurate diffusion coefficient (5.7x10(-6) cm2 s-1) of the drug molecules in reasonable (3 h) computation times. The model was validated using experimental data from in vitro dissolution experiments and provided accurate prediction of the drug release from the delivery system (root mean square error of 5%). The amount of drug entering the systemic circulation, computed from the predicted drug release in varying pH environments in the small bowel, was 15-24%. This range was in good agreement with clinical in vivo data (13-36%) obtained from literature. This research shows that in silico experiments using mechanistic models and stochastic approaches can be used for drug design and optimization and as a decision making tool for physicians.

Administration, Oral↗
PubMed2006

Flooding in GROMACS: accelerated barrier crossings in molecular dynamics.

The major bottleneck of today's atomistic molecular dynamics (MD) simulations is that because of the enormous computational effort involved, only processes at nanoseconds to microseconds time scales or faster can be studied directly. Unfortunately, apart from a few exceptions, relevant processes, such as chemical reactions or many large scale conformational transitions in proteins, occur at slower time scales and therefore are currently far out of reach for conventional MD. The flooding technique addresses this problem by inclusion of a flooding potential into the force field. This flooding potential locally destabilizes the educt state and thereby significantly accelerates the escape from the initial energy well without affecting the reaction pathway. Here, we summarize the theory and method for the computational chemistry community and detail the implementation within the official version 3.3 of the freely available MD program package GROMACS. Two examples shall demonstrate the application of flooding to accelerate conformational transitions and chemical reactions. The second example was carried out within a QM/MM framework.

Butanes↗
PubMed2000

Bending and adaptability to proteins of the cAMP DNA-responsive element: molecular dynamics contrasted with NMR.

DNA bending is assumed to play a crucial role during recognition of the cAMP-responsive element (CRE) by transcription factors. However, diverging results have been obtained for the bending direction of the unbound double helix. The refined NMR structures present a bend directed toward the minor groove, while biochemical methods conclude that there is a bend toward the major groove. The present 10-ns molecular dynamics (MD) simulation of d(GAGATGACGTCATCTC)(2), which contains the octamer CRE in its center, was carried out with AMBER in explicit water and counterions. It shows that CRE is a flexible segment, although it is bent slightly toward the major groove (7 degrees -8 degrees ) on the average. The MD structure agrees with both the biochemical results and unrefined NMR data. The divergence with the NMR refined structures suggests an improper electrostatic parameterization in the refinement software. The malleability of the central CpG is certainly the major contribution to the curving of the whole CRE segment in both the unbound and bound states. Comparison with the crystal structure of CRE bound to GCN4 shows that the deformation induced by the protein is concentrated mainly on the CpG step, rendering the bound structure of CRE closer to the structure of the 12-0 tetradecanoylphorbol-beta-acetate-responsive element.

Base Pairing↗
PubMed2005

Prediction of HIV-1 protease inhibitor resistance using a protein-inhibitor flexible docking approach.

Emergence of drug resistance remains one of the most challenging issues in the treatment of HIV-1 infection. Here we focus on resistance to HIV-1 protease inhibitors (PIs) at a molecular level, which can be analysed genotypically or phenotypically. Genotypic assays are based on the analysis of mutations associated with reduced drug susceptibility, but are problematic because of the numerous mutations and mutational patterns that confer drug resistance. Phenotypic resistance or susceptibility can be experimentally evaluated by measuring the amount of free drug bound to HIV-1 protease molecules, but this procedure is expensive and time-consuming. To overcome these problems, we have developed a docking protocol that takes protein-inhibitor flexibility into account to predict phenotypic drug resistance. For six FDA-approved Pls and a total of 1792 HIV-1 protease sequence mutants, we used a combination of inhibitor flexible docking and molecular dynamics (MD) simulations to calculate protein-inhibitor binding energies. Prediction results were expressed as fold changes of the calculated inhibitory constant (Ki), and the samples predicted to have fold-increase in calculated Ki above the fixed cut-off were defined as drug resistant. Our combined docking and MD protocol achieved accuracies ranging from 72-83% in predicting resistance/susceptibility for five of the six drugs evaluated. Evaluating the method only on samples where our predictions concurred with established knowledge-based methods resulted in increased accuracies of 83-94% for the six drugs. The results suggest that a physics-based approach, which is readily applicable to any novel PI and/or mutant, can be used judiciously with knowledge-based approaches that require experimental training data to devise accurate models of HIV-1 Pl resistance prediction.

Binding Sites↗
PubMed2002

A proposed 3D structure for crotamine based on homology building, molecular simulations and circular dichroism.

Crotamine, isolated from the venom of the South American rattlesnake Crotalus durissus terrificus is a strongly basic 42-amino acid polypeptide belonging to the small basic myotoxin family. As no tridimensional structure is available for this myotoxin subfamily, despite its important pharmacological interest, we propose in this paper a theoretical 3D model for crotamine. Starting from a homology modelling procedure, followed by intensive molecular dynamics (MD) simulations in water and complementary CD experiments, the designed 3D model is the first example of a tridimensional structure in this family of small basic myotoxins. Crotamine, therefore, belongs to a newly identified structural family presenting a common fold also found in beta-defensin and antopleurine-B. The proposed 3D model will be used for future calculations about crotamine aggregation and interaction with membranes.

Amino Acid Sequence↗
PubMed1997

Graphical visualization of mean hydration from molecular dynamics simulations.

How does one characterize water solvating a complex solute? Specific hydration of proteins and nucleic acids plays a key role in many biological processes. However, traditional pairwise descriptions of solvent structure (radial distribution functions, etc.) are incapable of adequately describing the hydration of these complex solutes. We have developed methods to visualize the average three-dimensional water structure surrounding a solute, as seen in a molecular dynamics (MD) simulation. Applications to simple solutes [sodium ion, N-methyl acetamide, 18-crown-6, (hydroxymethyl)phenols] are presented, and the extension of the method to larger molecules of biochemical interest is discussed.

Acetamides↗
PubMed2005

Langevin model of the temperature and hydration dependence of protein vibrational dynamics.

The modification of internal vibrational modes in a protein due to intraprotein anharmonicity and solvation effects is determined by performing molecular dynamics (MD) simulations of myoglobin, analyzing them using a Langevin model of the vibrational dynamics and comparing the Langevin results to a harmonic, normal mode model of the protein in vacuum. The diagonal and off-diagonal Langevin friction matrix elements, which model the roughness of the vibrational potential energy surfaces, are determined together with the vibrational potentials of mean force from the MD trajectories at 120 K and 300 K in vacuum and in solution. The frictional properties are found to be describable using simple phenomenological functions of the mode frequency, the accessible surface area, and the intraprotein interaction (the displacement vector overlap of any given mode with the other modes in the protein). The frictional damping of a vibrational mode in vacuum is found to be directly proportional to the intraprotein interaction of the mode, whereas in solution, the friction is proportional to the accessible surface area of the mode. In vacuum, the MD frequencies are lower than those of the normal modes, indicating intramolecular anharmonic broadening of the associated potential energy surfaces. Solvation has the opposite effect, increasing the large-amplitude vibrational frequencies relative to in vacuum and thus vibrationally confining the protein atoms. Frictional damping of the low-frequency modes is highly frequency dependent. In contrast to the damping effect of the solvent, the vibrational frequency increase due to solvation is relatively temperature independent, indicating that it is primarily a structural effect. The MD-derived vibrational dynamic structure factor and density of states are well reproduced by a model in which the Langevin friction and potential of mean force parameters are applied to the harmonic normal modes.

Computer Simulation↗