Abstract
Drug resistance of mutations in HIV-1 protease (PR) is the most severe challenge to the long-term efficacy of HIV-1 PR inhibitor in highly active antiretroviral therapy. To elucidate the molecular mechanism of drug resistance associated with mutations (D30N, I50V, I54M, and V82A) and inhibitor (GRL-0519) complexes, we have performed five molecular dynamics (MD) simulations and calculated the binding free energies using the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method. The ranking of calculated binding free energies is in accordance with the experimental data. The free energy spectra of each residue and inhibitor interaction for all complexes show a similar binding model. Analysis based on the MD trajectories and contribution of each residues show that groups R2 and R3 mainly contribute van der Waals energies, while groups R1 and R4 contribute electrostatic interaction by hydrogen bonds. The drug resistance of D30N can be attributed to the decline in binding affinity of residues 28 and 29. The size of Val50 is smaller than Ile50 causes the residue to move, especially in chain A. The stable hydrophobic core, including the side chain of Ile54 in the wild type (WT) complex, became unstable in I54M because the side chain of Met54 is flexible with two alternative conformations. The binding affinity of Ala82 in V82A decreases relative to Val82 in WT. The present study could provide important guidance for the design of a potent new drug resisting the mutation inhibitors.
Highlights
Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is caused by infection with the human immunodeficiency virus (HIV) [1]
HIV-1 PR has been an important target for anti-AIDS drug therapies
Two hundred snapshots taken from the last 40 ns (21–60 ns) of the molecular dynamics (MD) simulations at an interval of 200 ps were applied to calculate the entropic contribution. ∆EMM and ∆Gsolv were averaged on 800 snapshots, which were extracted from the last 40 ns of MD trajectories at intervals of 50 ps
Summary
Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is caused by infection with the human immunodeficiency virus (HIV) [1]. The drug-resistant mutations of PR continue to be a major problem in the treatment of AIDS [3]. TThhee mmoolleeccuullaarr mmeecchhaanniiccss PPooiissssoonn––BBoollttzzmmaannnn ssuurrffaaccee area (MM-PBSA) method is useful for calculating the binding free energies of a given protein– inhibitor complex. 2016, 17, 819 area (MM-PBSA) method is useful for calculating the binding free energies of a given protein–inhibitor complex. BTihnedidngecwoemrepdoesceodmipnotseerdacbtyiounsienngergies provtihdeeMinMs-iPgBhStAinmtoetPhRoda.nAdpGerR-rLe-s0id5u1e9’bsabsiisndeincogmmpeocsihtiaonnismmetshaonddwhaeslupseedlutcoidoabtaeinthtehedbruingd-irnegsistant mecfhraeeniesnmergoifems buettawtieoennsGtRoLG-0R5L19-0a5n1d9 iwnditihvidthuealinPtRerrpesriedtuaeti.oTnhoe fdtehceomenpeorsgedetiinctaenradctsiotrnuecntuerrgailesresults fromprtohveidMeDinssiigmhut lianttiooPnRs. and GRL-0519’s binding mechanisms and help elucidate the drug-resistant mechanism of mutations to GRL-0519 with the interpretation of the energetic and structural results. Of the two contributions (∆Gele+pol) of each mutated complex is more unfavorable than that of the WT complex. We have performed the comparisons of the free energy components between the WT and each single mutation to elucidate the drug resistance mechanism. The entropic contribution plays an important role in the I50V because the entropic contribution in I50V is obviously larger than in the WT
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