The goal of the project is to develop numerical methods and computational strategies to understand the energetics and dynamics of chemical reactions in complex environments and to apply them to chemically and biologically interesting systems. Using a combination of reactive molecular dynamics (RMD), improved force fields, potential energy surface ``morphing'' procedures, and electronic structure calculations, reactions including hydrogen/proton-transfer, ligand-binding and electron-coupled proton transfer are investigated at a quantitative level. The reactive molecular dynamics method, which was developed for rebinding reactions of diatomic ligands to myoglobin, I) will be generalized to treat enzymatic and rebinding reactions between arbitrary ligands and substrates and II) will be extended to electron-transfer reactions. Specific applications of reactive molecular dynamics include ligand binding in myoglobin, Cytochrome P450, and Azotobacter Vinelandii Ferredoxin I (FdI). These are systems for which detailed experimental data and information from previous simulations is available. More reliable intermolecular interaction potentials will be derived by ``morphing'' suitable zeroth-order potential energy surfaces. This strategy will be applied to problems from molecular spectroscopy to proton transfer in proteins (e.g. FdI). To improve the description of the electrostatic interaction between ligands and the surrounding protein in ligand-binding studies we currently develop and implement a multi-center/multi-moment description based on the distributed multipole analysis. For a broader ligand-binding study to test the multi-center/multi-moment electrostatics, HIV-I protease is a suitable system because a variety of experimentally determined binding constants for chemically different ligands are available.
