Mounir Tarek

The dynamics of protein hydration water: a quantitative comparison of molecular dynamics simulations and neutron-scattering experiments.

We present results from an extensive molecular dynamics simulation study of water hydrating the protein Ribonuclease A, at a series of temperatures in cluster, crystal, and powder environments. The dynamics of protein hydration water appear to be very similar in crystal and powder environments at moderate to high hydration levels. Thus, we contend that experiments performed on powder samples are appropriate for discussing hydration water dynamics in native protein environments. Our analysis reveals that simulations performed on cluster models consisting of proteins surrounded by a finite water shell with free boundaries are not appropriate for the study of the solvent dynamics. Detailed comparison to available x-ray diffraction and inelastic neutron-scattering data shows that current generation force fields are capable of accurately reproducing the structural and dynamical observables. On the time scale of tens of picoseconds, at room temperature and high hydration, significant water translational diffusion and rotational motion occur. At low hydration, the water molecules are translationally confined but display appreciable rotational motion. Below the protein dynamical transition temperature, both translational and rotational motions of the water molecules are essentially arrested. Taken together, these results suggest that water translational motion is necessary for the structural relaxation that permits anharmonic and diffusive motions in proteins. Furthermore, it appears that the exchange of protein-water hydrogen bonds by water rotational/librational motion is not sufficient to permit protein structural relaxation. Rather, the complete exchange of protein-bound water molecules by translational displacement seems to be required.

Distribution of Halothane in a Dipalmitoylphosphatidylcholine Bilayer from Molecular Dynamics Calculations

We report a 2-ns constant pressure molecular dynamics simulation of halothane, at a mol fraction of 50%, in the hydrated liquid crystal bilayer phase of dipalmitoylphosphatidylcholine. Halothane molecules are found to preferentially segregate to the upper part of the lipid acyl chains, with a maximum probability near the C(5) methylene groups. However, a finite probability is also observed along the tail region and across the methyl trough. Over 95% of the halothane molecules are located below the lipid carbonyl carbons, in agreement with photolabeling experiments. Halothane induces lateral expansion and a concomitant contraction in the bilayer thickness. A decrease in the acyl chain segment order parameters, S(CD), for the tail portion, and a slight increase for the upper portion compared to neat bilayers, are in agreement with several NMR studies on related systems. The decrease in S(CD) is attributed to a larger accessible volume per lipid in the tail region. Significant changes in the electric properties of the lipid bilayer result from the structural changes, which include a shift and broadening of the choline headgroup dipole (P-N) orientation distribution. Our findings reconcile apparent controversial conclusions from experiments on diverse lipid systems.

Effects of Anesthetics on the Structure of a Phospholipid Bilayer: Molecular Dynamics Investigation of Halothane in the Hydrated Liquid Crystal Phase of Dipalmitoylphosphatidylcholine

We report the results of constant temperature and pressure molecular dynamics calculations carried out on the liquid crystal (Lalpha) phase of dipalmitoylphosphatidylcholine with a mole fraction of 6.5% halothane (2-3 MAC). The present results are compared with previous simulations for pure dipalmitoylphosphatidylcholine under the same conditions (Tu et al., 1995. Biophys. J. 69:2558-2562) and with various experimental data. We have found subtle structural changes in the lipid bilayer in the presence of the anesthetic compared with the pure lipid bilayer: a small lateral expansion is accompanied by a modest contraction in the bilayer thickness. However, the overall increase in the system volume is found to be comparable to the molecular volume of the added anesthetic molecules. No significant change in the hydrocarbon chain conformations is apparent. The observed structural changes are in fair agreement with NMR data corresponding to low anesthetic concentrations. We have found that halothane exhibits no specific binding to the lipid headgroup or to the acyl chains. No evidence is obtained for preferential orientation of halothane molecules with respect to the lipid/water interface. The overall dynamics of the lipid-bound halothane molecules appears to be reminiscent of that of other small solutes (Bassolino-Klimas et al., 1995. J. Am. Chem. Soc. 117:4118-4129).

First-Principles Determination of Hybrid Bilayer Membrane Structure by Phase-Sensitive Neutron Reflectometry

The application of a new, phase-sensitive neutron reflectometry method to reveal the compositional depth profiles of biomimetic membranes is reported. Determination of the complex reflection amplitude allows the related scattering length density (SLD) profile to be obtained by a first-principles inversion without the need for fitting or adjustable parameters. The SLD profile so obtained is unique for most membranes and can therefore be directly compared with the SLD profile corresponding to the chemical compositional profile of the film, as predicted, for example, by a molecular dynamics simulation. Knowledge of the real part of the reflection amplitude, in addition to enabling the inversion, makes it possible to assign a spatial resolution to the profile for a given range of wavevector transfer over which the reflectivity data are collected. Furthermore, the imaginary part of the reflection amplitude can be used as a sensitive diagnostic tool for recognizing the existence of certain in-plane inhomogeneities in the sample. Measurements demonstrating the practical realization of this phase-sensitive technique were performed on a hybrid bilayer membrane (self-assembled monolayer of thiahexa (ethylene oxide) alkane on gold and a phospholipid layer) in intimate contact with an aqueous reservoir. Analysis of the experimental results shows that accurate compositional depth profiles can now be obtained with a spatial resolution in the subnanometer range, primarily limited by the background originating from the reservoir and the roughness of the films supporting substrate.

Effects of solvent damping on side chain and backbone contributions to the protein boson peak

We report a MD simulation study of the behavior of the boson peak of a globular protein in realistic powder environments corresponding to conditions of neutron scattering studies (hydrated at 150 K, dry at 150 K, and dry at 300 K). The temperature and hydration dependence of the boson peak, an excess of inelastic scattering intensity over the harmonic background at low frequency, are in excellent agreement with neutron scattering data on powder samples of several proteins. To gain further insight into the nature of boson peak, and its relation to hydration water, we have decomposed the inelastic spectrum into contributions from the protein backbone, nonpolar side chains in the interior of the protein, and polar side chains exposed to the solvent. We find that the boson peak arises from motions distributed throughout the protein, regardless of the conditions of temperature and hydration. Furthermore, the relative contribution from each part of the protein considered shows a similar temperature and hydratio...

Membrane Structural Perturbations Caused by Anesthetics and Nonimmobilizers: A Molecular Dynamics Investigation

The structural perturbations of the fully hydrated dimyristoyl-phosphatidylcholine bilayer induced by the presence of hexafluoroethane C(2F6), a nonimmobilizer, have been examined by molecular dynamics simulations and compared with the effects produced by halothane CF3CHBrCl, an anesthetic, on a similar bilayer (DPPC) (Koubi et al., Biophys. J. 2000. 78:800). We find that the overall structure of the lipid bilayer and the zwitterionic head-group dipole orientation undergo only a slight modification compared with the pure lipid bilayer, with virtually no change in the potential across the interface. This is in contrast to the anesthetic case in which the presence of the molecule led to a large perturbation of the electrostatic potential across to the membrane interface. Similarly, the analysis of the structural and dynamical properties of the lipid core are unchanged in the presence of the nonimmobilizer although there is a substantial increase in the microscopic viscosity for the system containing the anesthetic. These contrasting perturbations of the lipid membrane caused by those quite similarly sized molecules may explain the difference in their physiological effects as anesthetics and nonimmobilizers, respectively.

Molecular Dynamics Simulations of Supported Phospholipid/Alkanethiol Bilayers on a Gold(111) Surface

Molecular dynamics simulations have been used to investigate the structure of hybrid bilayers (HB) formed by dipalmitoylphosphatidylcholine (DPPC) lipid monolayers adsorbed on a hydrophobic alkanethiol self-assembled monolayer (SAM). The HB system was studied at 20 degrees C and 60 degrees C, and the results were compared with recent neutron reflectivity measurements (Meuse, C. W., S. Krueger, C. F. Majkrzak, J. A. Dura, J. Fu, J. T. Connor, and A. L. Plant. 1998. Biophys. J. 74:1388) and previous simulations of hydrated multilamellar bilayers (MLB) of DPPC (Tu, K., D. J. Tobias, and M. L. Klein. 1995. Biophys. J. 69:2558; and 1996. 70:595). The overall structures of the HBs are in very good agreement with experiment. The structure of the SAM monolayer is hardly perturbed by the presence of the DPPC overlayer. The DPPC layer presents characteristics very similar to the MLB gel phase at low temperature and to the liquid crystal phase at high temperature. Subtle changes have been found for the lipid/water interface of the HBs compared to the MLBs. The average phosphatidylcholine headgroup orientation is less disordered, and this produces changes in the electric properties of the HB lipid/water interface. These changes are attributed to the fact that the aqueous environment of the lipids in these unilamellar films is different from that of MLB stacks. Finally, examination of the intramolecular and whole-molecule dynamics of the DPPC molecules in the fluid phase HB and MLB membranes revealed that the reorientations of the upper part of the acyl chains (near the acyl ester linkage) are slower, the single molecule protrusions are slightly damped, and the lateral rattling motions are significantly reduced in the HB compared with the MLB.

Molecular dynamics studies of aqueous surfactants systems

Abstract Recent progress in the characterization of aqueous surfactant systems using molecular dynamics simulations is reviewed, and insights into the structure and dynamical behavior of three systems are presented. In the first example we study the formation of an ethanol monolayer at the air/water interface. The second example is an investigation of the structure and the dynamics of nanoscale aqueous droplets, similar to those encountered in nucleation of binary systems from the gaseous phase. Finally, we report recent results on attempts to follow the self assembly of micellar aggregates from surfactant monomers in solutions.

Molecular dynamics investigation of an ethanol-water solution

A molecular dynamics simulation of a 0.1 M ethanol-water solution with an air/solution interface was performed. Redistribution of ethanol molecules was observed during the simulation, which was initiated from a bulk solution. The results of the simulation show good agreement with surface tension measurements and the number density profiles of the ethanol excess from neutron reflectivity experiments. A depletion layer beneath the ethanol surface excess was revealed by the simulation. Ethanol molecules are oriented at the surface such that the alkyl group points out of the solution. The number of water molecules involved in the hydrogen bonding with the ethanol molecules decreases by a factor of 2 between the surface and the bulk.

Molecular dynamics studies of the hexagonal mesophase of sodium dodecylsulphate in aqueous solution

Molecular dynamics calculations using a recently proposed simulation methodology (Martyna, G. J., Tuckerman, M. E., Tobias, D. J., and Klein, M. L., 1996, Molec. Phys., 87, 1117) have been carried out to investigate the structural properties of the sodium dodecylsulphate (SDS)-water system in the lyotropic liquid crystalline mesophase E. The simulation system consisted of two cylindrical aggregates, each containing 128 dodecylsulphate anions, plus 256 sodium counterions and 4350 water molecules. The system had periodic boundary conditions and initially overall hexagonal symmetry. A 260ps trajectory was then generated at constant temperature (T = 333 K) and constant pressure (P = 0) using a new molecular dynamics package (PINY-MD), which utilizes a timestep almost an order of magnitude larger than the usual value. The structural and dynamic results are compared with previous simulations reported for quasi-spherical SDS micelles and experimental data on the same system. In agreement with experiment, the sim...