A study of the relationship between catalytic activity and flexibility in HIV-1 protease mutants by NMA and QM/MM

• Grant number: 13/04041-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2013
• End date: May 31, 2016
• Field of knowledge: Biological Sciences - Biophysics
• Principal Investigator: Paula Homem-de-Mello
• Grantee: Valderes de Conto
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

Since first cases of AIDS up to now, remarkable advances in HIV/AIDS treatment have been achieved. Although a effectiveness vaccine has not yet been developed, the highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of the patients. HIV-1 protease is a valuable drug target, as inhibition of PR activity results in immature noninfectious virions. The major challenge to HAART is the rapid evolution of drug resistance. Major mutations in PR are generally acquired early and lower the affinityfor the drug more than for the natural substrate but often resulting in a decreased viral replication fitness. Additional mutations can compensate for the deleterious effects of major drug resistance mutations, thus increasing the viral fitness. In previous studies, our group studied the effects of the single and doubles mutations on the flexibility behavior and hydrogen bond of the HIV-1 PR and their relationship to fitness. However, this was an indirect approach, since the fitness of the enzyme is directly related to its catalytic activity. Accordingly, in this project we use QM/MM based in structures generated by NMA to investigate the effect of mobility changes of the HIV-1 PR in its catalytic activity. This will be done in the context which includes the wild type and single and double mutants that can change and restore the flexibility behavior. In addition, a better understanding of thefailures/restoration processes of the fitness will give insight intothe design of new inhibitors.