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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040526-22
Application #
7821417
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
1988-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
22
Fiscal Year
2010
Total Cost
$271,143
Indirect Cost
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
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
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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
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
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
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
Hall, Michelle Lynn; Goldfeld, Dahlia A; Bochevarov, Arteum D et al. (2009) Localized orbital corrections for the calculation of barrier heights in density functional theory. J Chem Theory Comput 5:2996-3009
Schneebeli, Severin T; Hall, Michelle Lynn; Breslow, Ronald et al. (2009) Quantitative DFT modeling of the enantiomeric excess for dioxirane-catalyzed epoxidations. J Am Chem Soc 131:3965-73

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