The long term goal of this project is the development of computational methods that will enable accurate modeling of protein active site chemistry at an atomic level of detail, with a primary focus on metalloproteins. Such modeling will provide insight into biological functioning of metalloenzymes and transport proteins, and facilitate the design of pharmaceutically relevant compounds interacting with these systems. The computational methods that we are developing include new approaches to density functional theory, mixed quantum mechanics/molecular mechanics methods, sampling algorithms for treating protein conformational transitions, and algorithms to calculate overall free energy changes for chemical reactions of interest. Specific proteins to be studied in the proposed granting period include methane mono-oxygenase, cytochrome P450, and hemoglobin. Cytochrome P450, which plays a fundamental role in drug metabolism, will be a particular focus of the project. We will continue to work on understanding the fundamental mechanism of hydroxylation, but at the same time, building on promising preliminary results obtained over the past several years, will investigate the conformational plasticity of the active site which is a critical aspect of the ability of these enzymes to interact with a wide variety of compounds. A direct, health related goal of the project is to develop a suite of tools for creating a reliable structural and energetic model of pharmaceutically relevant compounds interacting with human P450 isoforms;such a model would be immediately useful the late stages of lead optimization to modify preclinical candidates which exhibit problems with P450 metabolism.
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