These are three major challenges in using computational methods to simulate protein and protein-ligand systems: (1) the need for improvement in the accuracy of the representation of the energy of the system; (2) the need for improvement in the sampling of both comformational and chemical space and (3) the need for better ways to combine quantum mechanical electronic structure and molecular mechanical methods to study enzyme catalyzed chemical reactions. We have made some advance in meeting these challenges in the last period of support and propose studies to further address them. We have developed a new force field for protein systems which, combined with a new approach to include long-range electrostatic effects, is a step forward in meeting challenge (1). But these is a clear need for more accurate short range electrostatic interactions and the inclusion of many-body effects - our proposed studies describe the development of models which contain these. We have shown that locally enhanced sampling (LES) to be very promising in calculation of loop structures and free energies. To address the conformational sampling challenge (2), we propose the continued development of LES methods and their application to antibody hypervariable loops, among others. Free energy calculations have been powerful in addressing the chemical sampling challenge (2), but they have been too computational intensive for many applications. We have developed a new qualitative free energy approach, PROFEC, which shows promise and we propose to develop a new method (MD/MC) that should broaden the applicability of free energy approaches to ligand and protein design problems. We have begun the development of a new, more powerful method to study enzyme catalysis, challenge (3), using a combination of high level ab initio calculation and classical free energy calculations. We propose to apply it to a variety of enzyme catalyzed reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029072-20
Application #
6351170
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Flicker, Paula F
Project Start
1982-02-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
20
Fiscal Year
2001
Total Cost
$203,790
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
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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