The present project will structurally and thermodynamically characterize many of the mutations in HIV- 1 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 ? about.-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 protency, 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 Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037660-07
Application #
6747703
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nunn, Michael
Project Start
1998-05-15
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2006-04-30
Support Year
7
Fiscal Year
2004
Total Cost
$313,650
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sturdevant, Christa Buckheit; Joseph, Sarah B; Schnell, Gretja et al. (2015) Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 11:e1004720
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