COMPUTER SIMULATION OF BIOMOLECULAR STRUCTURE, FUNCTION & DYNAMICS

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The MetaCenter proposal is geared towards understanding the structure, function and dynamics of biologically relevant systems. Specifically computer time is requested to reach the following goals: (1) We propose to use molecular dynamics (MD) simulations to probe the mechanism by which fusion peptides carry out their function. We have already carried out MD simulations on bilayer systems ( See Appendix B ) including a system that contains the experimentally well characterized tripeptide Ala-Phe-Ala. Our work on the Ala-Phe-Ala system has been quite successful in reproducing the order positioning of this peptide in the bilayer as well as reproducing the parameters of nearby lipid alkyl chains. Given our ability to model this well characterized system effectively we have begun to study small peptides that either facilitiate or inhibit fusogenic activity. (2) We propose to use potential of mean force simulations to obtain molecular-level insights into how a cation is captured by the ionophore valinomycin. From these simulations we will obtain a detailed picture regarding the energetic ( free energies, enthalpies, and entropies ) or the ion capture process as well as detailed structural insights. (3) Coupled density function/molecular mechanics (DF/MM) methods will be used to study a reaction mechanism in solution. We have recently developed the DF/MM method within our laboratory and have published preliminary work using this model. With the DF/MM method we will study the proton transfer reaction between water and hydroxide ion to obtain molecular-level insights into how solvent affects proton transfer reactions. In general, these methods represent and exciting new technique that will give molecular-level details regarding reactions in solution and in the future enzyme active sites.