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PubMed2003

Molecular dynamics simulations of the E1/E2 transmembrane domain of the Semliki Forest virus.

Transmembrane (TM) helix-helix interactions are important for virus budding and fusion. We have developed a simulation strategy that reveals the main features of the helical packing between the TM domains of the two glycoproteins E1 and E2 of the alpha-virus Semliki Forest virus and that can be extrapolated to sketch TM helical packing in other alpha-viruses. Molecular dynamics simulations were performed in wild-type and mutant peptides, both isolated and forming E1/E2 complexes. The simulations revealed that the isolated wild-type E1 peptide formed a more flexible helix than the rest of peptides and that the wild-type E1/E2 complex consists of two helices that intimately pack their N-terminals. The residues located at the interhelical interface displayed the typical motif of the left-handed coiled-coils. These were small and medium residues as Gly, Ala, Ser, and Leu, which also had the possibility to form interhelical Calpha-H...O hydrogen bonds. Results from the mutant complexes suggested that correct packing is a compromise between these residues at both E1 and E2 interhelical interfaces. This compromise allowed prediction of E1-E2 contact residues in the TM spanning domain of other alphaviruses even though the sequence identity of E2 peptides is low in this domain.

Amino Acid Motifs↗
PubMed2005

Possible pathway(s) of testosterone egress from the active site of cytochrome P450 2B1: a steered molecular dynamics simulation.

To probe the possible substrate exit channel(s) in cytochrome P450 (P450) 2B1 and to clarify the role of residues previously identified by site-directed mutagenesis, a homology model was constructed based on the X-ray crystal structure of a P450 2B4-inhibitor complex. Testosterone was docked into the active site of P450 2B1 and was then pulled out through three putative channels using steered molecular dynamics simulations. The results indicated that of the three channels, the "solvent channel," lined by helices E, F, and I and the beta3 hairpin, required the largest rupture force and backbone motion, which rendered it unlikely as an exit route. The relatively small rupture forces and backbone motions for the other two channels suggested them as possible candidates for testosterone passage. The opening of channel 1, located between helices G and I and the B'-C loop, is characterized by rotation of the aromatic ring of Phe297 together with a bending of the B'-C loop. The opening of channel 2, penetrating through the B'-C loop/B' helix, is achieved by an expansion of this region and a small displacement of the backbone. Interestingly, during the egress of testosterone along channel 1, Phe297 and Phe108 appear to act as two clamps to stabilize testosterone binding and prevent it from leaving the active site. Phe115 acts as a gatekeeper for channel 2. These results are in agreement with previous site-directed mutagenesis experiments.

Amino Acid Sequence↗
PubMed1998

Cofilin and gelsolin segment-1: molecular dynamics simulation and biochemical analysis predict a similar actin binding mode.

An understanding of the actin-depolymerizing function attributed to members of the ADF/cofilin/destrin superfamily requires a structural model of these proteins in complex with actin. As a step toward defining actin-cofilin interactions, the complex of yeast cofilin with monomeric actin was predicted, starting with the actin-gelsolin segment-1 binding mode recently suggested for the actin-destrin complex. After refinement by molecular dynamics simulation, the structure of cofilin converged in a new binding mode that required only minimal changes induced in the actin-cofilin interface. The predicted complex exhibits strong interactions between the N termini of actin and cofilin, mediated by a salt bridge of cofilin Arg3 with actin Asp1. The forming of this salt bridge could be prevented by the phosphorylation of cofilin Ser4, which is believed to inhibit cofilin depolymerization activity. Recent mutagenesis studies, crosslinking experiments and peptide binding studies are consistent with the predicted model of the actin-cofilin complex. The structural homology between cofilin and gelsolin segment-1 binding to actin was confirmed experimentally by two types of competitive binding assays.

Actin Depolymerizing Factors↗
PubMed2005

Homology modeling and molecular dynamics simulations of the mu opioid receptor in a membrane-aqueous system.

Three types of opioid receptors-mu, delta, and kappa-belong to the rhodopsin subfamily in the G protein-coupled receptor superfamily. With the recent characterization of the high-resolution X-ray crystal structure of bovine rhodopsin, considerable attention has been focused on molecular modeling of these transmembrane proteins. In this study, a homology model of the mu opioid receptor was constructed based on the X-ray crystal structure of bovine rhodopsin. A phospholipid bilayer was built around the receptor, and two water layers were placed on both surfaces of the lipid bilayer. Molecular-dynamics simulations were carried out by using CHARMM for the entire system, which consisted of 316 amino acid residues, 92 phospholipid molecules, 8327 water molecules, and 11 chloride counter ions-40 931 atoms altogether. The whole system was equilibrated for 250 ps followed by another 2 ns dynamic simulation. The opioid ligand naltrexone was docked into the optimized model, and the critical amino acid residues for binding were identified. The mu opioid receptor homology model optimized in a complete membrane-aqueous system should provide a good starting point for further characterization of the binding modes for opioid ligands. Furthermore, the method developed herein will be applicable to molecular model building to other opioid receptors as well as other GPCRs.

Animals↗
PubMed2005

Distorted five-fold coordination of Cu2+(aq) from a Car-Parrinello molecular dynamics simulation.

The solvation shell structure and dynamics of a single Cu2+ ion in a periodic box with 32 water molecules under ambient conditions has been investigated using Car-Parrinello molecular dynamics simulations in a time-window of 18 ps. Five-fold coordination with four equidistant equatorial water molecules at 2.00 A and one axial water molecule at 2.45 A from the Cu2+ ion is found. A "hole" without water molecules is found on the opposite side of the axial water. The ion-water bonding character for the equatorial water molecules is different from that of the axial water molecules, as shown by a localized orbital analysis of the electronic structure. Moreover, the calculated OD stretching vibrational band for the equatorial water molecules lies ca. 175 cm-1 below the axial-water band, in good agreement with experimental data. The equatorial-water band lies below, and the axial-water band above, the pure liquid D2O band, also in agreement with experimental data.

Algorithms↗
PubMed2004

Molecular dynamics simulations and oxidation rates of methionine residues of granulocyte colony-stimulating factor at different pH values.

To understand the connection between the conformation of a protein molecule and the oxidation of its methionine residues, we measured the rates of oxidation of methionine residues by H(2)O(2) in granulocyte colony-stimulating factor (G-CSF) as a function of pH and also studied the structural properties of this protein as a function of pH via molecular dynamics simulations. We found that each of the four methionine groups in G-CSF have significant and different rates of oxidation as a function of pH. Moreover, Met(1), in the unstructured N-terminal region, has a rate of oxidation as low as half that of free methionine. The structural properties of G-CSF as a function of pH are evaluated in terms of properties such as hydrogen bonding, deviations from X-ray structure, helical/helical packing, and the atomic covariance fluctuation matrix of alpha-carbons. We found that dynamics (structural fluctuations) are essential in explaining oxidation and that a static picture, such as that resulting from X-ray data, fails in this regard. Moreover, the simulation results also indicate that the solvent-accessible area, traditionally used to measure solvent accessibility of a protein site, of the sulfur atom of methionine residues does not correlate well with the rate of oxidation. Instead, we identified a structural property, average two-shell water coordination number, that correlates well with measured oxidation rates.

Amino Acid Sequence↗
PubMed2005

Structure of dense hydrogen fluoride gas from neutron diffraction and molecular dynamics simulations.

The gas phase of hydrogen fluoride has been investigated by neutron diffraction experiments at three different particle densities. All investigated states are within the liquid-gas coexistence region of hydrogen fluoride. From the obtained diffraction data we deduced information about the local structure of the gas phase, which consists of small agglomerates. This has been expected as liquid hydrogen fluoride forms the strongest hydrogen bonds known. Molecular dynamics simulations with a modified potential have been carried out for all experimentally investigated states. The results confirmed that the size of the formed agglomerates in the gas phase is growing with increasing density of the gas phase.

Journal Article↗
PubMed1986

Molecular dynamics simulations of cooling in laser-excited heme proteins.

In transient optical experiments the absorbed photon raises the vibrational temperature of the chromophore. In heme proteins at room temperature conversion of a 530-nm photon into vibrational energy is estimated to raise the temperature of the heme by 500-700 K. Cooling of the heme is expected to occur mainly by interacting with the surrounding protein. We report molecular dynamics simulations for myoglobin and cytochrome c in vacuo that predict that this cooling occurs on the ps time scale. The decay of the vibrational temperature is nonexponential with about 50% loss occurring in 1-4 ps and with the remainder in 20-40 ps. These results predict the presence of nonequilibrium vibrational populations that would introduce ambiguity into the interpretation of transient ps absorption and Raman spectra and influence the kinetics of sub-ns geminate recombination.

Biophysical Phenomena↗
PubMed2004

Membrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations.

Lipid-modified membrane-binding proteins are essential in signal transduction events of the cell, a typical example being the GTPase ras. Recently, membrane binding of a doubly lipid-modified heptapeptide from the C-terminus of the human N-ras protein was studied by spectroscopic techniques. It was found that membrane binding is mainly due to lipid chain insertion, but it is also favored by interactions between apolar side chains and the hydrophobic region of the membrane. Here, 10 explicit solvent molecular dynamics simulations for a total time of about 150 ns are used to investigate the atomic details of the peptide-membrane association. The 16:0 peptide lipid chains are more mobile than the 14:0 phospholipid chains, which is in agreement with (2)H NMR experiments. Peptide-lipid and peptide-solvent interactions, backbone and side-chain distributions, as well as the effects of lipidated peptide insertion onto the structure, and dynamics of a 1,2-dimyristoylglycero-3-phosphocholine bilayer are described. The simulation results validate the structural model proposed by the analysis of spectroscopic data and highlight the main aspects of the insertion mechanism. The peptide in the membrane is rather rigid over the simulation time scale of about 10 ns, but different partially extended conformations devoid of backbone hydrogen bonds are observed in different trajectories.

Computer Simulation↗
PubMed1998

NMR structure refinement and dynamics of the K+-[d(G3T4G3)]2 quadruplex via particle mesh Ewald molecular dynamics simulations.

The solution structure and dynamical properties of the potassium-stabilized, hairpin dimer quadruplex formed by the oligonucleotide d(G3T4G3) have been elucidated by a combination of high-resolution NMR and molecular dynamics simulations. Refinement calculations were carried out both in vacuo, without internally coordinated K+ cations, and in explicit water, with internally coordinated K+ cations. In the latter case, the electrostatic interactions were calculated using the particle mesh Ewald (PME) method. The NMR restraints indicate that the K+ quadruplex has a folding arrangement similar to that formed by the same oligonucleotide in the presence of sodium, but with significant local differences. Unlike the Na+ quadruplex, the thymine loops found in K+ exhibit considerable flexibility, and appear to interconvert between two preferred conformations. Furthermore, the NMR evidence points toward K+-stabilized guanine quartets of slightly larger diameter relative to the Na+-stabilized structure. The characteristics of the quartet stem are greatly affected by the modeling technique employed: caged cations alter the size and symmetry of the quartets, and explicit water molecules form hydration spines within the grooves. These results provide insight into those factors that determine the overall stability of hairpin dimer quadruplexes and the effects of different cations in modulating the relative stability of the dimeric hairpin and linear, four-stranded, quadruplex forms.

Base Sequence↗
PubMed2005

Sequence-dependent conformational energy of DNA derived from molecular dynamics simulations: toward understanding the indirect readout mechanism in protein-DNA recognition.

Sequence dependence of DNA conformation plays a crucial role in its recognition by proteins and ligands. To clarify the relationship between sequence and conformation, it is necessary to quantify the conformational energy and specificity of DNA. Here, we make a systematic analysis of dodecamer DNA structures including all the 136 unique tetranucleotide sequences at the center by molecular dynamics simulations. Using a simplified conformational model with six parameters to describe the geometry of adjacent base pairs and harmonic potentials along these coordinates, we estimated the equilibrium conformational parameters and the harmonic potentials of mean force for the central base-pair steps from many trajectories of the simulations. This enabled us to estimate the conformational energy and the specificity for any given DNA sequence and structure. We tested our method by using sequence-structure threading to estimate the conformational energy and the Z-score as a measure of specificity for many B-DNA and A-DNA crystal structures. The average Z-scores were negative for both kinds of structures, indicating that the potential of mean force from the simulation is capable of predicting sequence specificity for the crystal structures and that it may be used to study the sequence specificity of both types of DNA. We also estimated the positional distribution of conformational energy and Z-score within DNA and showed that they are strongly position dependent. This analysis enabled us to identify particular conformations responsible for the specificity. The presented results will provide an insight into the mechanisms of DNA sequence recognition by proteins and ligands.

Base Sequence↗
PubMed2005

"Like-charge attraction" between anionic polyelectrolytes: molecular dynamics simulations.

"Like-charge attraction" is a phenomenon found in many biological systems containing DNA or proteins, as well as in polyelectrolyte systems of industrial importance. "Like-charge attraction" between polyanions is observed in the presence of mobile multivalent cations. At a certain limiting concentration of cations, the negatively charged macroions cease to repel each other and even an attractive force between the anions is found. With classical molecular dynamics simulations it is possible to elucidate the processes that govern the attractive behavior with atomistic resolution. As an industrially relevant example we study the interaction of negatively charged carboxylate groups of sodium polyacrylate molecules with divalent cationic Ca2+ counterions. Here we show that Ca2+ ions initially associate with single chains of polyacrylates and strongly influence sodium ion distribution; shielded polyanions approach each other and eventually "stick" together (precipitate), contrary to the assumption that precipitation is initially induced by intermolecular Ca2+ bridging.

Journal Article↗
PubMed2006

Equation of state of nitrogen (N2) at high pressures and high temperatures: molecular dynamics simulation.

Nitrogen equation of state at pressures up to 30 GPa (300 kbars) and temperatures above 800 K was studied by molecular dynamics (MD) simulations. The dynamics of the N(2) molecules is treated in hard rotor approximation, i.e., it accounts both translational and rotational degrees of freedom. The rotational motion of the N(2) molecule is treated assuming constant moment of inertia of the nitrogen molecule. The new MD program fully accounts anisotropic molecular nitrogen interaction. The N(2)-N(2) interaction potential has been derived by van der Avoird et al. [J. Chem. Phys. 84, 1629 (1986)] using the results of high precision Hartree-Fock ab initio quantum mechanical calculations. The potential, fully accounts rotational symmetry of the N(2)-N(2) system, by employing 6-j Wigner symbols, i.e., preserving full rotational symmetry of the system. Various numerical algorithms were tested, in order to achieve the energy preservation during the simulation. It has been demonstrated that the standard Verlet algorithm was not preserving the energy for the standard MD time step, equal to 5x10(-16) s. Runge-Kutta fourth order method was able to preserve the energy within 10(-4) relative error, but it requires calculation of the force four times for each time step and therefore it is highly inefficient. A predictor-corrector method of the fifth order (PC5) was found to be efficient and precise and was therefore adopted for the simulation of the molecular nitrogen properties at high pressure. Singer and Fincham algorithms were tested and were found to be as precise as PC5 algorithm and they were also used in the simulation of the equation of state. Results of MD simulations are in very good agreement with the experimental data on nitrogen equation of state at pressures below 1 GPa (10 kbars). For higher pressures, up to 30 GPa (300 kbars), i.e., close to molecular nitrogen stability limit, determined by Nellis et al. [Phys. Rev. Lett. 85, 1262 (1984)], the obtained numerical results provide new data of the experimentally unexplored region. These data were formulated in the analytical form of pressure-density-temperature equation of state.

Journal Article↗
PubMed2006

Diffusion in binary gas mixtures studied by NMR of hyperpolarized gases and molecular dynamics simulations.

The dependence of the individual mean square displacement of rare gases in binary mixtures is studied by a combined experimental and theoretical approach. We show that the diffusion constant can be varied in a considerable range by changing the molar fractions of the mixtures. On the experimental side, NMR diffusion measurements are done on hyperpolarized 3He and 129Xe, mixed with several inert buffer gases, in the presence of a magnetic field gradient. The results are compared to diffusion coefficients obtained from atomistic molecular dynamics simulations based on Lennard-Jones type potentials of the corresponding gas mixtures, and to appropriate analytical expressions, yielding very good mutual agreement. This study is the first quantitative validation of the effects of the mutual interactions between gas particles on the individual diffusion properties. It is shown that the dependency of gas phase diffusion properties on the local chemical environment may not be neglected, e.g. in diffusion-controlled chemical reactions.

Complex Mixtures↗
PubMed2005

A comparative study of cluster-surface collisions: Molecular-dynamics simulations of (H2O)1000 and (SO2)1000.

A classical molecular-dynamics study of (H2O)1000 and (SO2)1000 clusters impacting with velocities between 6 x 10(2) and 8 x 10(3) ms at normal incidence on a repulsive target is presented. Using the ratio of total kinetic energy to total binding energy of the cluster as a scaling parameter, a general description of the fragmentation dynamics as well as the final fragment size distributions is achieved for the different systems. With increasing ratio, the angular distribution of the emitted monomers rapidly shifts from isotropic to anisotropic. At the highest investigated velocities, a tendency to recover more isotropic distributions is observed. Comparable transient compression of the impacting cluster is reached, on the other hand, for the same, unscaled collision velocities in both systems. For both H2O and SO2 the obtained internal temperatures of the cluster fragments are found to be independent of impact energy and close to the boiling temperature of the respective systems.

Journal Article↗
PubMed2005

Coarse-grained molecular-dynamics simulations of the self-assembly of pentablock copolymers into micelles.

Multiblock polymers in aqueous solution, where one or several blocks are hydrophobic, exhibit a rich variety of phases and states of aggregation. In this paper, we investigate a pentablock system ABCBA, where the B block is always hydrophilic and the A and C blocks have varying degrees of hydrophobicity depending on external conditions. We report coarse-grained molecular-dynamics simulations where the solvent is included explicitly and monomers interact via a 6-9 Lennard Jones potential function. The hydrophobic interaction is modeled by tuning the parameter controlling the strength of the interaction between the hydrophobic monomers and the solvent. We investigate the structure and morphology of the micelles for two concrete situations representing changes in temperature and the pH level. The simulated system is directly relevant to a recently synthesized pentablock system consisting of a triblock Pluronic with an added pH-sensitive end group [B. C. Anderson et al., Macromolecules 36, 1670 (2003)].

Journal Article↗
PubMed2004

Molecular-dynamics simulations with explicit hydrodynamics I: on the friction coefficients of deformed polymers.

We implement large-scale Molecular-Dynamics (MD) simulations which incorporate hydrodynamic interactions via the inclusion of explicit Lennard-Jones solvent to examine the behaviour of polymer chains in sieving media. We begin by examining the friction coefficients of polymers in long-lived states responsible for inducing length-dependent mobility, i.e., allowing separation of polymers (or polyelectrolytes) by molecular weight. In particular, the conformations we examine occur in devices which utilize arrays of molecular obstacles or dilute solutions of polymers. We compare the results from our MD simulations with expressions from macroscopic hydrodynamics for four specific cases: i) a random coil excluded-volume Zimm polymer, ii) a rigid polymer moving perpendicular to its major axis iii) a rigid polymer moving parallel to its major axis and iv) a rigid polymer, folded at different points along its contour. We also examine the behaviour of the friction coefficient of a fully flexible molecule pulled by its middle monomer as a function of an applied force F and show that there are several distinct frictional regimes.

Journal Article↗
PubMed2003

A prokaryotic glutamate receptor: homology modelling and molecular dynamics simulations of GluR0.

GluR0 is a prokaryotic homologue of mammalian glutamate receptors that forms glutamate-activated, potassium-selective ion channels. The topology of its transmembrane (TM) domain is similar to that of simple potassium channels such as KcsA. Two plausible alignments of the sequence of the TM domain of GluR0 with KcsA are possible, differing in the region of the P helix. We have constructed homology models based on both alignments and evaluated them using 6 ns duration molecular dynamics simulations in a membrane-mimetic environment. One model, in which an insertion in GluR0 relative to KcsA is located in the loop between the M1 and P helices, is preferred on the basis of lower structural drift and maintenance of the P helix conformation during simulation. This model also exhibits inter-subunit salt bridges that help to stabilise the TM domain tetramer. During the simulation, concerted K(+) ion-water movement along the selectivity filter is observed, as is the case in simulations of KcsA. K(+) ion exit from the central cavity is associated with opening of the hydrophobic gate formed by the C-termini of the M2 helices. In the intact receptor the opening of this gate will be controlled by interactions with the extramembranous ligand-binding domains.

Amino Acid Sequence↗