Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation
While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated 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 energ...
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MDPI AG
2021-05-01
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| Online Access: | https://www.mdpi.com/1999-4915/13/5/920 |
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| author | Qinfang Sun Ronald M. Levy Karen A. Kirby Zhengqiang Wang Stefan G. Sarafianos Nanjie Deng |
| author_facet | Qinfang Sun Ronald M. Levy Karen A. Kirby Zhengqiang Wang Stefan G. Sarafianos Nanjie Deng |
| author_sort | Qinfang Sun |
| collection | DOAJ |
| description | While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated 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. |
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| id | doaj.art-c8b17cfcdf6b46e4aa486a13d0012ca3 |
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| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T11:23:18Z |
| publishDate | 2021-05-01 |
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| spelling | doaj.art-c8b17cfcdf6b46e4aa486a13d0012ca32023-11-21T19:54:57ZengMDPI AGViruses1999-49152021-05-0113592010.3390/v13050920Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid MutationQinfang Sun0Ronald M. Levy1Karen A. Kirby2Zhengqiang Wang3Stefan G. Sarafianos4Nanjie Deng5Center for Biophysics and Computational Biology and Department of Chemistry, Temple University, Philadelphia, PA 19122, USACenter for Biophysics and Computational Biology and Department of Chemistry, Temple University, Philadelphia, PA 19122, USALaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USALaboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Chemistry and Physical Sciences, Pace University, New York, NY 10038, USAWhile drug resistance mutations can often be attributed to the loss of direct or solvent-mediated 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.https://www.mdpi.com/1999-4915/13/5/920HIV-1 capsiddrug resistance mutationfree energy simulationmolecular dynamicsprotein reorganization |
| spellingShingle | Qinfang Sun Ronald M. Levy Karen A. Kirby Zhengqiang Wang Stefan G. Sarafianos Nanjie Deng Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation Viruses HIV-1 capsid drug resistance mutation free energy simulation molecular dynamics protein reorganization |
| title | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation |
| title_full | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation |
| title_fullStr | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation |
| title_full_unstemmed | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation |
| title_short | Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation |
| title_sort | molecular dynamics free energy simulations reveal the mechanism for the antiviral resistance of the m66i hiv 1 capsid mutation |
| topic | HIV-1 capsid drug resistance mutation free energy simulation molecular dynamics protein reorganization |
| url | https://www.mdpi.com/1999-4915/13/5/920 |
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