The long range goal of this project is to develop and apply theoretical computer simulation methods to enable an accurate prediction of the structures and interaction free energies of small molecules with proteins and the activation free energies of enzyme catalyzed reactions. Such a predictive model would enable one to design selective and effective inhibitors for enzymes and to design more effective enzyme catalysts. The ability to design effective enzyme inhibitors would have enormous implications for human health and the design of enzyme catalysts would be very useful in biotechnological applications. To reach the long range goal, studies are proposed to develop efficient strategies for conformational analysis of molecules, to more accurately represent the energies of molecular interactions, to develop methods to calculate energy differences between related systems and to more effectively couple quantum mechanical and molecular mechanical/dynamical methods. These methods will be developed and tested on a variety of protein systems, i.e., the serine and cysteine protease hydrolytic enzymes, enzymes which interact with highly changed substrates such as triose phosphate isomerase, adenylate kinase and staphloccocal nuclease, trp repressor protein and T4 lyzozyme. The specific objectives in the studies on these proteins include the elucidation of the complete free energy profile for enzyme catalysis (serine proteases and cysteine proteases) and comparable biomimetic and non-catalyzed reaction profiles, which should lead to an understanding of what makes enzyme catalysis unique; secondly, simulations to understand protein conformational changes (adenylate kinase and trp repressor) in terms of the molecular forces of the system; and finally, the development of methods to simulate and understand the principles in and design of thermally more stable proteins (myoglobin and T4 lyzozyme).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029072-12
Application #
3276543
Study Section
Special Emphasis Panel (SSS (C))
Project Start
1982-02-01
Project End
1994-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Minehardt, T J; Kollman, P A; Cooke, R et al. (2006) The open nucleotide pocket of the profilin/actin x-ray structure is unstable and closes in the absence of profilin. Biophys J 90:2445-9
Wang, Junmei; Kang, Xinshan; Kuntz, Irwin D et al. (2005) Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA. J Med Chem 48:2432-44
Duan, Yong; Wu, Chun; Chowdhury, Shibasish et al. (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24:1999-2012
Chong, Lillian T; Bandyopadhyay, Pradipta; Scanlan, Thomas S et al. (2003) Direct hydroxide attack is a plausible mechanism for amidase antibody 43C9. J Comput Chem 24:1371-7
Naber, Nariman; Minehardt, Todd J; Rice, Sarah et al. (2003) Closing of the nucleotide pocket of kinesin-family motors upon binding to microtubules. Science 300:798-801
Gouda, Hiroaki; Kuntz, Irwin D; Case, David A et al. (2003) Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods. Biopolymers 68:16-34
Masukawa, Kevin M; Kollman, Peter A; Kuntz, Irwin D (2003) Investigation of neuraminidase-substrate recognition using molecular dynamics and free energy calculations. J Med Chem 46:5628-37
Minehardt, Todd J; Marzari, Nicola; Cooke, Roger et al. (2002) A classical and ab initio study of the interaction of the myosin triphosphate binding domain with ATP. Biophys J 82:660-75
Massova, Irina; Kollman, Peter A (2002) pKa, MM, and QM studies of mechanisms of beta-lactamases and penicillin-binding proteins: acylation step. J Comput Chem 23:1559-76
Dixon, Richard W; Radmer, Randall J; Kuhn, Bernd et al. (2002) Theoretical and experimental studies of biotin analogues that bind almost as tightly to streptavidin as biotin. J Org Chem 67:1827-37

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