Physical chemistry. Molecules at the edge.
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News↗
Biomedical subjects
P J Rossky
Publications and source records attributed to P J Rossky.
Simulation of an S(N)1 reaction in supercritical water.
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Journal Article↗
The effect of vicinal polar and charged groups on hydrophobic hydration.
The use of a linear relationship between free energy of hydrophobic hydration and solvent-accessible apolar surface area has been helpful in interpreting the thermodynamics of biological macromolecules. However, a recent study (Y.-K. Cheng, P. J. Rossky, Nature 1998, Vol. 392, pp. 696-699) has established a substantial enthalpic dependence on biomolecular surface topography, originating from solvent hydrogen-bonding loss in a restrictive geometry. In this study, we use molecular dynamics simulations of 2-Zn insulin in water solvent to explore the further effect of vicinal polar or charged groups on hydrophobic hydration at a biomolecular surface. In contrast to the case for solvent more isolated from such polar solute influences, the binding energies of the water that is proximal to the hydrophobic dimeric interface of insulin and vicinal to polar and charged groups are comparable to the bulk solvent value, a result of compensating interaction primarily with the solute counterions. The results suggest a special importance for such polar/charged groups in biological processes involving hydrophobic surface regions of restricted geometry and also suggest a general route for tuning the hydrophobicity of interfaces.
Computer Simulation↗
Hydrophobic hydration of amphipathic peptides.
Biomolecular surfaces and interfaces are commonly found with apolar character. The hydrophobic effect thus plays a crucial role in processes involving association with biomolecular surfaces in the cellular environment. By computer simulation, we compared the hydrogen bonding structures and energetics of the proximal hydration shells of the monomer and dimer from a recent study of an extrinsic membrane peptide, melittin. The two peptides were studied in their amphipathic alpha-helical forms, which possess extended hydrophobic surfaces characterized by different topography. The topography of the peptide-water interface was found to be critical in determining the enthalpic nature of hydrophobic hydration. This topographical dependence has far-reaching implications in the regulation of bioactivities in the presence of amphipathicity. This result also engenders reconsideration of the validity of using free energy parameters that depend solely on the chemical nature of constituent moieties in characterizing hydrophobic hydration of proteins and biomolecules in general.
Animals↗
Surface topography dependence of biomolecular hydrophobic hydration.
Many biomolecules are characterized by surfaces containing extended nonpolar regions, and the aggregation and subsequent removal of such surfaces from water is believed to play a critical role in the biomolecular assembly in cells. A better understanding of the hydrophobic hydration of biomolecules may therefore yield new insights into intracellular assembly. Conventional views hold that the hydration shell of small hydrophobic solutes is clathrate-like, characterized by local cage-like hydrogen-bonding structures and a distinct loss in entropy. The hydration of extended nonpolar planar surfaces, however, appears to involve structures that are orientationally inverted relative to clathrate-like hydration shells, with unsatisfied hydrogen bonds that are directed towards the hydrophobic surface. Here we present computer simulations of the interaction between the polypeptide melittin and water that demonstrate that the two different hydration structures also exist near a biomolecular surface. We find that the two structures are distinguished by a substantial difference in the water-water interaction enthalpy, and that their relative contributions depend strongly on the surface topography of the melittin molecule: clathrate-like structures dominate near convex surface patches, whereas the hydration shell near flat surfaces fluctuates between clathrate-like and less-ordered or inverted structures. The strong influence of surface topography on the structure and free energy of hydrophobic hydration is likely to hold in general, and will be particularly important for the many biomolecules whose surfaces contain convex patches, deep or shallow concave grooves and roughly planar areas.
Computer Simulation↗
Influence of an antiviral compound on the temperature dependence of viral protein flexibility and packing: a molecular dynamics study.
The antiviral activity of compounds that bind an internal pocket of picornaviruses is due in part to stabilization of the protein capsid and inhibition of the uncoating process required for virus replication. Information on the basis for this structural stabilization of the virus capsid is important to elucidate the mechanism of antiviral action and provide insights into the disassembly process. It has been proposed that this stabilization is entropically based, since binding the nonpolar antiviral compound increases the compressibility, and thus the conformational flexibility, of the virus. Such a proposal predicts a difference in the temperature dependence of the atomic positional fluctuations for free virus and drug-bound virus; nonpolar interactions are weaker and less directional, and would give rise to greater conformational disorder at low temperature. Further, the transition that has been observed in globular proteins to a state resembling a frozen liquid, in which the protein is considered "trapped" in potential energy wells, is predicted to occur at lower temperature when the antiviral compound is bound. Results described here from computer simulations of rhinovirus over a range in temperature show these predicted changes in conformational disorder and the temperature of the transition in mobility. In addition to providing independent support for the above proposal for antiviral activity, these results indicate that the mobility transition of a protein can be controlled by the binding of an appropriate ligand, an effect not previously reported.
Antiviral Agents↗
Dynamics of chemical processes in polar solvents.
Understanding solution-phase chemistry requires a microscopic description of the electronic structure of the reacting molecules, and of the complex influence of the solvent medium on the reaction energetics and dynamics. Processes involving reactant charge-transfer are of particular importance in chemistry and biochemistry, and are strongly influenced by polar media. Recent advances in experimental ultrafast laser spectroscopy and in computer simulation are working together to provide insight into the underlying molecular principles governing this class of processes in solution.
Computer Simulation↗
Hydrophobic and ionic hydration phenomena.
Computer simulation offers an increasing opportunity to examine the details of solvation structure for well-defined solution models. One can characterize idealized models that exemplify specific aspects of solution behavior or those that realistically model systems experimentally difficult to access. As an example from the first category, results are presented for the aqueous solvation structure and solvent hydrogen bonding in the presence of a small apolar solute, and these are contrasted with the quite different behavior observed for a large apolar surface. As an example from the second category, structural results are presented for hydration of an excess electron in bulk water. These latter results, obtained via recent path integral simulation methods, manifest significant solvent structural disruption compared to the case of a simple ion, due to the irregular and fluctuating shape of the quantum solute.
Chemical Phenomena↗