The present project will structurally and thermodynamically characterize many of the mutations in HIV protease that confer resistance to ritonavir. The nature of many of these mutations suggest the involvement of structural rearrangements, solvation effects, or entropic factors, requiring rigorous molecular simulation techniques to model. This project will entail advancing the X-dynamics scheme to computationally explore mutations at multiple sites in a single mutation. As X-dynamics is a modified molecular dynamics algorithm, it contains the necessary elements to study these phenomena. Specifically, explicit solvent is used, bound and unbound simulations are considered, and full protein motion is simulated (allowing detection of changes in protein structure and dynamics). Furthermore, sampling is performed in a thermodynamically meaningful ensemble, such that relative free energies of binding can be obtained. In addition to providing insight into the mechanisms of resistance and potentially allowing for prediction of drug modifications that may improve potency, the methodologies used may prove useful in predicting the resistance profiles of lead compounds in future drug optimization scenarios.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI049673-01
Application #
6339793
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Bridges, Sandra H
Project Start
2001-03-01
Project End
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$33,260
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Guvench, Olgun; Price, Daniel J; Brooks 3rd, Charles L (2005) Receptor rigidity and ligand mobility in trypsin-ligand complexes. Proteins 58:407-17
Price, Daniel J; Brooks 3rd, Charles L (2002) Modern protein force fields behave comparably in molecular dynamics simulations. J Comput Chem 23:1045-57