The investigator aims to develop reliable, theoretically coherent computational models for non-covalent binding, focusing on the association of proteins and small, drug-like molecules. Specifically, this will involve (1) Elaboration of the thermodynamic theory of binding; (2) Development and testing of a novel numerical approach to evaluating configuration integrals using the predominant states approximation (3) Testing of models of binding by the ability of an energy function to pick out the correct bound conformation of a ligand from many plausible alternatives. (4) Development and testing of improved models of solvation in binding calculations using continuum Poisson-Boltzmann solvent models. (5) Evaluation of simple models of binding to serve as benchmarks so that a more complex model will only be used if more accurate. (6) Optimization of a new, accurate method for predicting protonation states of titratable groups in proteins, and use in binding calculations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM054053-04
Application #
2910231
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of MD Biotechnology Institute
Department
Type
Organized Research Units
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21202
David, L; Luo, R; Gilson, M K (2001) Ligand-receptor docking with the Mining Minima optimizer. J Comput Aided Mol Des 15:157-71
Mardis, K L; Luo, R; Gilson, M K (2001) Interpreting trends in the binding of cyclic ureas to HIV-1 protease. J Mol Biol 309:507-17
Luo, R; Head, M S; Given, J A et al. (1999) Nucleic acid base-pairing and N-methylacetamide self-association in chloroform: affinity and conformation. Biophys Chem 78:183-93
Trylska, J; Antosiewicz, J; Geller, M et al. (1999) Thermodynamic linkage between the binding of protons and inhibitors to HIV-1 protease. Protein Sci 8:180-95
Forsyth, W R; Gilson, M K; Antosiewicz, J et al. (1998) Theoretical and experimental analysis of ionization equilibria in ovomucoid third domain. Biochemistry 37:8643-52
Given, J A; Gilson, M K (1998) A hierarchical method for generating low-energy conformers of a protein-ligand complex. Proteins 33:475-95
Gilson, M K; Given, J A; Head, M S (1997) A new class of models for computing receptor-ligand binding affinities. Chem Biol 4:87-92