Molecular dynamics free energy simulations reveal the mechanism for the antiviral resistance of the m66i hiv-1 capsid mutation

Qinfang Sun, Ronald M. Levy, Karen A. Kirby, Zhengqiang Wang, Stefan G. Sarafianos, Nanjie Deng

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While drug resistance mutations can often be attributed to the loss of direct or solventmediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83-and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.

Original languageEnglish (US)
Article number920
Issue number5
StatePublished - 2021

Bibliographical note

Funding Information:
Funding: This study was supported in part by National Institutes of Health grant U54 AI150472 to RML and SGS, R35 GM132090 to RML, R01 AI120860 to SGS and ZW, and by Bridge funds from Pace University to ND. SGS acknowledges funding from the Nahmias-Schinazi Distinguished Chair in Research. The calculations were run on the XSEDE allocation resource TGMCB100145 and a shared computing cluster at Temple University supported by National Institutes of Health S10 OD020095. X-ray data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions, and equipment grants (S10 RR25528, S10 RR028976 and S10 OD027000) from the National Institutes of Health. The Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility is operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Drug resistance mutation
  • Free energy simulation
  • HIV-1 capsid
  • Molecular dynamics
  • Protein reorganization


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