Systematic Molecular Dynamics, MM–PBSA, and Ab Initio Approaches to the Saquinavir Resistance Mechanism in HIV-1 PR Due to 11 Double and Multiple Mutations

• DOI: 10.1021/jp502687q
• Publication Date: 2014-07-18T18:11:40Z
• Authors: Haralambos Tzoupis; Georgios Leonis; Aggelos Avramopoulos; Thomas Mavromoust...; Manthos G. Papado...
• Keywords: Saquinavir

Mutations in the human immunodeficiency virus (HIV) enable replication even when appropriate antiretroviral therapy is followed, thus leading to emergence of drug resistance. In a previous work, we systematically examined seven single mutations that are associated with saquinavir (SQV) resistance HIV-1 protease (Tzoupis, H.; Leonis, G.; Mavromoustakos, T.; Papadopoulos, M. G. J. Chem. Theory Comput. 2013, 9, 1754–1764). Herein, extend our analysis, which includes double (G48V-V82A, L10I-G48V, G48V-L90M, I84V-L90M, L10I-V82A, L10I-L63P, A71V-G73S) and four multiple (L10I-L63P-A71V, L10I-G48V-V82A, G73S-I84V-L90M, L10I-L63P-A71V-G73S-I84V-L90M) SQV–HIV-1 PR mutant complexes, an attempt generalize findings formulate main elements SQV mechanism protease. On basis molecular dynamics (MD), mechanics Poisson–Boltzmann surface area (MM–PBSA), ab initio computational approaches, identified specific features constitute at level: low flexibility binding cavity preservation hydrogen bonding (HB) van der Waals interactions between several active-site (Gly27/27′, Asp29/29′/30/30′, especially Asp25/25′) flap (Ile50/50′, Gly48/48′) residues contribute significantly efficient binding. The total enthalpy loss all mutants mostly due region. Furthermore, it was observed mutation accumulation may induce stabilization flaps through enhanced HB lead improved inhibition (e.g., complexes containing L10I, G48V, L63P, I84V, or L90M mutations). It also concluded permanent closure obtained independently driven by Waals, nonpolar, exchange-energy contributions. Importantly, indicated optimal positioning structure tightly coupled, since small changes geometry affect energy greatly. results theoretical approaches agreement experimental evidence provide reliable description PR.