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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
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Columbia University (N.Y.)
Other Domestic Higher Education
New York
United States
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Friesner, Richard A; Abel, Robert; Goldfeld, Dahlia A et al. (2013) Computational methods for high resolution prediction and refinement of protein structures. Curr Opin Struct Biol 23:177-84
Zeiske, Tim; Stafford, Kate A; Friesner, Richard A et al. (2013) Starting-structure dependence of nanosecond timescale intersubstate transitions and reproducibility of MD-derived order parameters. Proteins 81:499-509
Miller, Edward B; Murrett, Colleen S; Zhu, Kai et al. (2013) Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program. J Chem Theory Comput 9:1846-4864
Li, Jianing; Abel, Robert; Zhu, Kai et al. (2011) The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins 79:2794-812
Li, Jianing; Schneebeli, Severin T; Bylund, Joseph et al. (2011) IDSite: An accurate approach to predict P450-mediated drug metabolism. J Chem Theory Comput 7:3829-3845
Bochevarov, Arteum D; Li, Jianing; Song, Woon Ju et al. (2011) Insights into the different dioxygen activation pathways of methane and toluene monooxygenase hydroxylases. J Am Chem Soc 133:7384-97
Wang, Lingle; Friesner, Richard A; Berne, B J (2011) Replica exchange with solute scaling: a more efficient version of replica exchange with solute tempering (REST2). J Phys Chem B 115:9431-8
Bochevarov, Arteum D; Friesner, Richard A; Lippard, Stephen J (2010) The prediction of Fe Mössbauer parameters by the density functional theory: a benchmark study. J Chem Theory Comput 6:3735-3749
Tian, Li; Friesner, Richard A (2009) QM/MM Simulation on P450 BM3 Enzyme Catalysis Mechanism. J Chem Theory Comput 5:1421-1431
Wang, Lingle; Abel, Robert; Friesner, Richard A et al. (2009) Thermodynamic properties of liquid water: an application of a nonparametric approach to computing the entropy of a neat fluid. J Chem Theory Comput 5:1462-1473

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