Abstract

We will carry out calculations in four main areas. First, we describe a pattern-matching approach to prediction of protein secondary structure. This program can be coupled to the tertiary packing algorithms of Cohen et.al. to produce protein-like structures. In the best case with proteins that have been studied crystallographically, discrepancies of ca. 4 angstroms are observed. Methods of reducing these errors are evaluated. Second, we seek a detailed model for the motions of ligands in proteins. Conventional molecular dynamics and trajectory calculations will be compared to methods that reveal packing defects and channels in proteins in a direct way. Third, we wish to extend our docking calculations to macromolecular interactions and to systematic structural comparison of sets of bioactive compounds. Fourth, methods are discussed to evaluate the potential functions used in molecular mechanics and molecular dynamics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031497-06
Application #
3279538
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1983-03-01
Project End
1991-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Kang, Xinshan; Shafer, Richard H; Kuntz, Irwin D (2004) Calculation of ligand-nucleic acid binding free energies with the generalized-born model in DOCK. Biopolymers 73:192-204
Fujii, Naoaki; Haresco, Jose J; Novak, Kathleen A P et al. (2003) A selective irreversible inhibitor targeting a PDZ protein interaction domain. J Am Chem Soc 125:12074-5
Greenbaum, Doron C; Arnold, William D; Lu, Felice et al. (2002) Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design. Chem Biol 9:1085-94
Huo, Shuanghong; Wang, Junmei; Cieplak, Piotr et al. (2002) Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: insight into structure-based ligand design. J Med Chem 45:1412-9
Laboissiere, Martha C A; Young, Malin M; Pinho, Rilva G et al. (2002) Computer-assisted mutagenesis of ecotin to engineer its secondary binding site for urokinase inhibition. J Biol Chem 277:26623-31
Pegg, S C; Haresco, J J; Kuntz, I D (2001) A genetic algorithm for structure-based de novo design. J Comput Aided Mol Des 15:911-33
Aronov, A M; Munagala, N R; Kuntz, I D et al. (2001) Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase. Antimicrob Agents Chemother 45:2571-6
Ewing, T J; Makino, S; Skillman, A G et al. (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des 15:411-28
Lamb, M L; Burdick, K W; Toba, S et al. (2001) Design, docking, and evaluation of multiple libraries against multiple targets. Proteins 42:296-318
Sullivan, D C; Kuntz, I D (2001) Conformation spaces of proteins. Proteins 42:495-511

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