title: Understanding the HIV-1 protease nelfinavir resistance mutation D30N in subtypes B and C through molecular dynamics simulations.
abstract: A major concern in the antiretroviral (ARV) treatment of HIV infections with protease inhibitors (PI) is the emergence of resistance, which results from the selection of distinct mutations within the viral protease (PR) gene. Among patients who do not respond to treatment with the PI nelfinavir (NFV), the D30N mutation is often observed. However, several reports have shown that D30N emerges with different frequencies in distinct HIV-1 genetic forms or subtypes. In the present work, we analyzed the binding of NFV and the Gag substrate CA/p2 to PR from HIV-1 subtypes B and C through molecular dynamics (MD) simulations. The wild-type and drug-resistant D30N mutants were investigated in both subtypes. The compensatory mutations N83T and N88D, observed in vitro and in vivo when subtype C acquires D30N, were also studied. D30N appears to facilitate conformational changes in subtype B PR, but not in that from subtype C, and this could be associated with disestablishment of an alpha-helical region of the PR. Furthermore, the total contact areas of NFV or the CA/p2 substrate with the mutant PR correlated with changes in the resistance patterns and replicative capacity. Finally, we observed in our MD simulations that mutant PR proteins show different patterns for hydrophobic/van der Waals contact. These findings suggest that different molecular mechanisms contribute to resistance, and we propose that a single mutation has distinct impacts on different HIV-1 subtypes.
authors.affiliation: Laboratório Nacional de Computação Científica, Petrópolis, Brazil.
authors.forename: Rosemberg O
authors.initials: RO
authors.lastname: Soares
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Batista
authors.forename: Mauricio G S
authors.initials: MG
authors.lastname: Costa
authors.forename: Laurent E
authors.initials: LE
authors.lastname: Dardenne
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Pascutti
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Soares
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D019888:Nelfinavir / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013379:Substrate Specificity / Q000187:drug effects; D013499:Surface Properties / Q000187:drug effects; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019888:Nelfinavir