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PubMed2005

Atomistic molecular-dynamics simulations of the size and shape of polyethylene in hexane at infinite dilution.

Parameters characteristic of size and shape of single polyethylene chains consisting of 15-60 monomer units dissolved in hexane are calculated by use of molecular-dynamics simulations based on a fully atomistic representation of the system. Results are compared with corresponding calculations in vacuum as well as Monte Carlo simulations of coarse-grained chains. The major concern of the study is a careful check of actual limits and possibilities of atomistic simulations of global properties of polymers. As expected such simulations are still restricted to rather small chain lengths but are already large enough to obey the characteristics of polymer coils.

Journal Article↗
PubMed2004

Molecular dynamics simulations of electrostatic layer-by-layer self-assembly.

Electrostatic assembly of multilayered thin films through sequential adsorption of polyions in layer-by-layer fashion utilizes the strong electrostatic attraction between oppositely charged molecules. We perform molecular dynamics simulations of multilayers of flexible polyelectrolytes around a charged spherical particle. Our simulations establish that the charge reversal after each deposition step is a crucial factor for the steady layer growth. The multilayers appear to be nonequilibrium structures.

Algorithms↗
PubMed2000

Molecular dynamics simulation studies of lipid bilayer systems.

The main structural element of biological membranes is a liquid-crystalline lipid bilayer. Other constituents, i.e. proteins, sterols and peptides, either intercalate into or loosely attach to the bilayer. We applied a molecular dynamics simulation method to study membrane systems at various levels of compositional complexity. The studies were started from simple lipid bilayers containing a single type phosphatidylcholine (PC) and water molecules (PC bilayers). As a next step, cholesterol (Chol) molecules were introduced to the PC bilayers (PC-Chol bilayers). These studies provided detailed information about the structure and dynamics of the membrane/water interface and the hydrocarbon chain region in bilayers built of various types of PCs and Chol. This enabled studies of membrane systems of higher complexity. They included the investigation of an integral membrane protein in its natural environment of a PC bilayer, and the antibacterial activity of magainin-2. The latter study required the construction of a model bacterial membrane which consisted of two types of phospholipids and counter ions. Whenever published experimental data were available, the results of the simulations were compared with them.

Animals↗
PubMed1993

Conformational analysis of arachidonic and related fatty acids using molecular dynamics simulations.

Arachidonic acid has recently gained attention as a result of current evidence indicating that it may play the role of a 'second messenger' in signal transduction processes. In order to gain insight into the mechanism behind its action, quenched molecular dynamics simulations were performed on arachidonic (20:4) and related fatty acids: linoleic (18:2), oleic (18:1), arachidic (20:0), and stearic (18:0). The angle-iron structure, representative of arachidonic acid in the crystal or very-low-temperature state, readily gave way at higher temperature to a dominant hairpin structure whereby the COOH end of arachidonic acid comes into close proximity with the C14-15 pi-bond resulting in a packed pi-bond-rich loop. The lowest energy conformer for arachidonic acid was found to be 10.65 kcal/mol below that of the energy-minimized crystal structure. In the case of saturated fatty acids, the crystal all-trans conformation remained the lowest energy form. Analysis of conformational energy contours for carbon-carbon torsion angles representative of fatty acids suggest that the flexibility of arachidonic acid is, in part, a result of the relative torsional freedom of C-C (single) bonds located between or adjacent to C = C (double) bonds. It is hypothesized that the ability of arachidonic acid to form packed structures with curved regions containing pi-bonds may allow for hydrophobic interactions with proteins, and/or hydrogen bonding between the pi-bonds of arachidonic acid and polar groups of the protein structures.

Arachidonic Acid↗
PubMed1995

Osmotic permeability in a molecular dynamics simulation of water transport through a single-occupancy pore.

The aim of this work is to determine plausible values for the rate constants of kinetic models representing water transport through narrow pores. We present here the results of molecular dynamics simulations of the movement of water molecules through a single-site hydrophilic pore. The system consists of a rectangular box of water molecules, some of which are positionally restrained so as to act as a membrane. This membrane separates two compartments where water molecules move freely; one of the positions in the membrane is initially vacant (the 'single-site pore'), but can be occupied by mobile molecules. To analyze the results, we represented the pore by a two-state kinetic diagram in which the vacant and occupied states are linked by transitions corresponding to the binding and release of water molecules. The mean occupancy and vacancy times directly yield the rate constants of binding and release, which in turn yield the osmotic water permeability coefficient per pore pf. We also compute the apparent activation energies delta E* for the rate constants and for pf. The pf value was (1.56 +/- 0.04).10(-11) cm3/s (at 307 K), which is much larger than those determined for CHIP28 and for gramicidin A (of about 10(-13) and 10(-14) cm3/s, respectively). These values were compared with those arising from a model of a symmetric single-file pore through which one-vacancy-mediated water transport takes place. The model yields an expression for pf as a function of the rate constants and of the number of molecular positions (n) in the file. When n = 1, this expression becomes the one corresponding to the single-site pore studied in our current simulation. Using the rate constants of binding and release derived from our simulation, the pf values are consistent with an occupancy value of 5-6 found for gramicidin A, and with occupancies of 4-7 that can be estimated for the single-file pore of a recently proposed model for CHIP28. delta E* for pf is 3.0 kcal/mol, a value similar to that determined for CHIP28. Hence, the system simulated here appears plausible and can be used to mimic some physical properties of water transport through biological pores.

Biological Transport↗
PubMed2000

Molecular-dynamics simulation of two-dimensional thermophoresis

A numerical technique is presented for the thermal force exerted on a solid particle by a gaseous medium between two flat plates at different temperatures, in the free molecular or transition flow. This is a two-dimensional molecular-dynamics simulation of hard disks in a inhomogeneous thermal environment. All steady-state features exhibited by the compressible hard-disk gas are shown to be consistent with the expected behaviors. Moreover the thermal force experienced by a large solid disk is investigated, and compared to the analytical case of cylinders moving perpendicularly to the constant temperature gradient for an infinite Knudsen number and in an infinite medium. We show precise examples of how this technique can be used simply to investigate more difficult practical problems, in particluar the influence of nonlinear gradients for large applied differences of temperature, of proximity of the walls, and of smaller Knudsen numbers.

Journal Article↗
PubMed1994

Molecular dynamics simulation of equine infectious anemia virus Tat protein in water and in 40% trifluoroethanol.

Two molecular dynamics (MD) simulations were performed in order to increase the understanding of the dependence of protein conformation on solvent environment. The protein used for these simulations is the transcriptional activator of the equine infectious anemia virus (EIAV-Tat). The structure of this protein has been determined by nuclear magnetic resonance (NMR) in aqueous solution (Willbold et al., Science 264, 1584 (1994)) and in 40% (v/v) trifluoroethanol (TFE) (Sticht et al., Eur. J. Biochem., submitted) showing considerable differences in the stability of the secondary structure elements. In order to investigate the influence of the solvent MD simulations (300 K: 200 ps) were carried out in water and in a solvent containing 40% (v/v) TFE. In both simulations the structure as determined in 40% TFE by NMR showing three-helices and a tight type II turn, was used as the initial structure. The MD simulations clearly indicate a decreased stability of the secondary structure elements in aqueous environment as made obvious by larger atomic motions and stronger fluctuations in the length of the hydrogen bonds. Complete unfolding of the helices was not observed on a 200 ps timescale. The root mean square deviation (RMSD) values of the backbone atoms after 200 ps simulation compared to the starting structure underline the strong influence of the solvent on the protein stability. This RMSD value is 1.95 A for the simulation in water and 1.29 A for the simulation in TFE/water. This result supports the notion that TFE acts as a secondary structure inducing and stabilizing solvent. The differences apparent from the MD simulations are in good agreement with the data derived from NMR measurements, showing the relevance of MD as a method for estimating conformational and dynamical properties of proteins.

Amino Acid Sequence↗
PubMed2006

Molecular dynamics simulation of glycine zwitterion in aqueous solution.

A classical molecular dynamics method was used to study the modifications of the solution structure and the properties of glycine zwitterion in aqueous solution due to the increase of glycine zwitterion concentration and the incorporation of Na(+) and Cl(-) ions to the solution. The glycine zwitterion had fundamentally a hydrophilic behavior at infinite dilution, establishing around six hydrogen bonds with the water molecules that surrounded it, which formed a strong hydration layer. Because of the increase of glycine zwitterion concentration, the hydration structure became more compact and the quantity of water molecules bound to this molecule decreased. The Na(+) ion bound to the CO(2) group of glycine, while the Cl(-) ion bound mainly to the NH(3) group of this molecule. The integration of the ions to the hydration layer of the glycine zwitterion produced modifications in the orientational correlation between atoms of glycine zwitterion and water that surrounded them and an increase of the approaches between the glycine zwitterion molecules. The incorporation of ions to the solution also produced changes in the water-water orientational correlation. Decreases of the water-water hydrogen bonds and diffusion coefficient of all molecules were observed when the glycine zwitterion concentration increased and when the ions were incorporated to the solution.

Chlorine↗
PubMed2005

Molecular dynamics simulation of sperm whale myoglobin: effects of mutations and trapped CO on the structure and dynamics of cavities.

The results of extended (80-ns) molecular dynamics simulations of wild-type and YQR triple mutant of sperm whale deoxy myoglobin in water are reported and compared with the results of the simulation of the intermediate(s) obtained by photodissociation of CO in the wild-type protein. The opening/closure of pathways between preexistent cavities is different in the three systems. For the photodissociated state, we previously reported a clear-cut correlation between the opening probability and the presence of the photolyzed CO in the proximity of the passage; here we show that in wild-type deoxy myoglobin, opening is almost random. In wild-type deoxy myoglobin, the passage between the distal pocket and the solvent is strictly correlated to the presence/absence of a water molecule that simultaneously interacts with the distal histidine side chain and the heme iron; conversely, in the photodissociated myoglobin, the connection with the bulk solvent is always open when CO is in the vicinity of the A pyrrole ring. In YQR deoxy myoglobin, the mutated Gln(E7)64 is stably H-bonded with the mutated Tyr(B10)29. The essential dynamics analysis unveils a different behavior for the three systems. The motion amplitude is progressively restricted in going from wild-type to YQR deoxy myoglobin and to wild-type myoglobin photoproduct. In all cases, the principal motions involve mainly the same regions, but their directions are different. Analysis of the dynamics of the preexisting cavities indicates large fluctuations and frequent connections with the solvent, in agreement with the earlier hypothesis that some of the ligand may escape from the protein through these pathways.

Animals↗
PubMed1998

Molecular dynamics simulation of glycoprotein-glycans of immunoglobulin G and immunoglobulin M.

Glycoprotein-glycans have recently been implicated to play a variety of functional roles. The same glycan chain have been found complexed with proteins of diverse functions. In this article two such glycan chains found attached to Fc regions of immunoglobulin G and immunoglobulin M have been studied. An extensive simulated annealing procedure have been adopted to arrive at a low-energy minimum of the two oligosaccharides. Molecular dynamics simulations have been performed to study the flexibility of the glycosidic linkages. It was found that both glycan chains can undergo conformational transitions and adopt folded and extended conformations. The two beta (1-2) linkages of complex-type glycan had been found to prefer different conformational regime and the terminal fucose linked to the GlcNAc residue drastically modifies the GlcNAc beta (1-4) GlcNAc linkage conformation. In the high-mannose type glycan chain alpha (1-3) linkages can induce flexibility in addition to the alpha (1-6) linkages. The results have been compared with recent experimental nmr and fluorescence energy transfer data.

Carbohydrate Sequence↗
PubMed2004

Continuum description of ionic and dielectric shielding for molecular-dynamics simulations of proteins in solution.

We extend our continuum description of solvent dielectrics in molecular-dynamics (MD) simulations, which has provided an efficient and accurate solution of the Poisson equation, to ionic solvents as described by the linearized Poisson-Boltzmann (LPB) equation. We start with the formulation of a general theory for the electrostatics of an arbitrarily shaped molecular system, which consists of partially charged atoms and is embedded in a LPB continuum. This theory represents the reaction field induced by the continuum in terms of charge and dipole densities localized within the molecular system. Because these densities cannot be calculated analytically for systems of arbitrary shape, we introduce an atom-based discretization and a set of carefully designed approximations. This allows us to represent the densities by charges and dipoles located at the atoms. Coupled systems of linear equations determine these multipoles and can be rapidly solved by iteration during a MD simulation. The multipoles yield the reaction field forces and energies. Finally, we scrutinize the quality of our approach by comparisons with an analytical solution restricted to perfectly spherical systems and with results of a finite difference method.

Binding Sites↗
PubMed2006

Molecular dynamics simulations of NAD+-induced domain closure in horse liver alcohol dehydrogenase.

Horse liver alcohol dehydrogenase is a homodimer, the protomer having a coenzyme-binding domain and a catalytic domain. Using all available x-ray structures and 50 ns of molecular dynamics simulations, we investigated the mechanism of NAD+-induced domain closure. When the well-known loop at the domain interface was modeled to its conformation in the closed structure, the NAD+-induced domain closure from the open structure could be simulated with remarkable accuracy. Native interactions in the closed structure between Arg369, Arg47, His51, Ala317, Phe319, and NAD+ were seen to form at different stages during domain closure. Removal of the Arg369 side-chain charge resulted in the loss of the tendency to close, verifying that specific interactions do help drive the domains closed. Further simulations and a careful analysis of x-ray structures suggest that the loop prevents domain closure in the absence of NAD+, and a cooperative mechanism operates between the subunits for domain closure. This cooperative mechanism explains the role of the loop as a block to closure because in the absence of NAD+ it would prevent the occurrence of an unliganded closed subunit when the other subunit closes on NAD+. Simulations that started with one subunit open and one closed supported this.

Alcohol Dehydrogenase↗
PubMed2005

Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations.

A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II Ki values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar Ki values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a Ki value of 35 nM.

Animals↗
PubMed2004

Molecular dynamics simulation study of the interaction of trehalose with lipid membranes.

The interactions of the cryoprotective agent trehalose with a lipid membrane made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine at 323 K were studied by means of molecular dynamics simulations. It was observed that trehalose binds to the phospholipid headgroups with its main axis parallel to the membrane normal. Trehalose establishes hydrogen bonds with the carbonyl and phosphate groups and replaces water molecules from the lipid headgroup. Notably, the number of hydrogen bonds (HBs) that the membrane made with its environment was conserved after trehalose binding. The HBs between lipid and trehalose have a longer lifetime than those established between lipid and water. The binding of the sugar does not produce changes either in the lipid area or in the lipid order parameter. The effect of trehalose on the dipole potential is in agreement with experimental results. The contribution of the different components to the membrane dipole potential was analyzed. It was observed that the binding of trehalose produces changes in the different components and the sugar itself contributes to the surface potential due to the polarization of its hydroxyl in the interface.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Hydrogen motions in the alpha-relaxation regime of poly(vinyl ethylene): a molecular dynamics simulation and neutron scattering study.

The hydrogen motion in poly(vinyl ethylene) (1,2-polybutadiene) in the alpha-relaxation regime has been studied by combining neutron spin echo (NSE) measurements on a fully protonated sample and fully atomistic molecular dynamics simulations. The almost perfect agreement between experiment and simulation results validates the simulated cell. A crossover from Gaussian to non-Gaussian behavior is observed for the intermediate scattering function obtained from both NSE measurements and simulations. This crossover takes place at unusually low Q values, well below the first maximum of the static structure factor. Such anomalous deviation from Gaussian behavior can be explained by the intrinsic dynamic heterogeneity arising from the differences in the dynamics of the different protons in this system. Side group hydrogens show a markedly higher mobility than main chain protons. Taking advantage of the simulations we have investigated the dynamic features of all different types of hydrogens in the sample. Considering each kind of proton in an isolated way, deviations from Gaussian behavior are also found. These can be rationalized in the framework of a simple picture based on the existence of a distribution of discrete jumps underlying the atomic motions in the alpha process.

Journal Article↗
PubMed2005

Adiabatic molecular-dynamics-simulation-method studies of kinetic friction.

An adiabatic molecular-dynamics method is developed and used to study the Muser-Robbins model for dry friction (i.e., nonzero kinetic friction in the slow sliding speed limit). In this model, dry friction between two crystalline surfaces rotated with respect to each other is due to mobile molecules (i.e., dirt particles) adsorbed at the interface. Our adiabatic method allows us to quickly locate interface potential-well minima, which become unstable during sliding of the surfaces. Since dissipation due to friction in the slow sliding speed limit results from mobile molecules dropping out of such unstable wells, our method provides a way to calculate dry friction, which agrees extremely well with results found by conventional molecular dynamics for the same system, but our method is more than a factor of 10 faster.

Journal Article↗
PubMed2004

Modelling of the complex between a 15-residue peptide from mSos2 and the N-terminal SH3 domain of Grb2 by molecular-dynamics simulation.

Under specific conditions, the complex formed by the adaptor protein Grb2 and the guanine-nucleotide exchange factor Sos2 is responsible for the activation of Ras, a low-molecular-weight GTPase involved in the control of cell proliferation and differentiation. The interaction between the N-terminal SH3 domain of the mouse Grb2 and one of its potential target sequences in the mouse, Sos2, a 15-residue peptide corresponding to residues 1264-1278, had been studied by NMR. However, the resulting data provided very limited information on the structure of the peptide and its interaction with the protein. Here, we present results from a molecular-dynamics simulation aimed at producing a realistic, atomic model for the interaction between the N-terminal SH3 domain of Grb2 and the SPLLPKLPPKTYKRE peptide from Sos2. In the simulation, the peptide adopts an extended conformation over the protein's binding surface. The proposed polyproline-type-II helicity appears only locally, and the peptide displays substantial flexibility. It is found that the peptide residues Lys10 to Tyr12 could be responsible for most of the specificity of the interaction.

Amino Acid Sequence↗
PubMed2006

Molecular dynamics simulation of liquid water confined inside graphite channels: dielectric and dynamical properties.

Electric and dielectric properties and microscopic dynamics of liquid water confined between graphite slabs are analyzed by means of molecular dynamics simulations for several graphite-graphite separations at ambient conditions. The electric potential across the interface shows oscillations due to water layering, and the overall potential drop is about -0.28 V. The total dielectric constant is larger than the corresponding value for the bulklike internal region of the system. This is mainly due to the preferential orientations of water nearest the graphite walls. Estimation of the capacitance of the system is reported, indicating large variations for the different adsorption layers. The main trend observed concerning water diffusion is 2-fold: on one hand, the overall diffusion of water is markedly smaller for the closest graphite-graphite separations, and on the other hand, water molecules diffuse in interfaces slightly slower than those in the bulklike internal areas. Molecular reorientational times are generally larger than those corresponding to those of unconstrained bulk water. The analysis of spectral densities revealed significant spectral shifts, compared to the bands in unconstrained water, in different frequency regions, and associated to confinement effects. These findings are important because of the scarce information available from experimental, theoretical, and computer simulation research into the dielectric and dynamical properties of confined water.

Journal Article↗