Accurate Ensemble Molecular Dynamics Binding Free Energy Ranking of Multidrug-Resistant HIV-1 Proteases

2010 ◽  
Vol 50 (5) ◽  
pp. 890-905 ◽  
Author(s):  
S. Kashif Sadiq ◽  
David W. Wright ◽  
Owain A. Kenway ◽  
Peter V. Coveney
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Multidrug Resistant ◽  
Hiv 1

Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions

RSC Advances ◽  
2016 ◽  
Vol 6 (63) ◽  
pp. 58573-58585 ◽  
Author(s):  
Jianzhong Chen
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Binding Free Energy ◽  
Resistance Mechanisms ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Probe Drug ◽  
Dynamics Simulations ◽  
Hiv 1

Molecular dynamics simulation and binding free energy calculations were used to probe drug resistance of HIV-1 protease mutations toward inhibitors.

scholarly journals Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 920
Author(s):  
Qinfang Sun ◽  
Ronald M. Levy ◽  
Karen A. Kirby ◽  
Zhengqiang Wang ◽  
Stefan G. Sarafianos ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Energy Cost ◽  
Binding Free Energy ◽  
Resistance Mutation ◽  
Side Chain ◽  
Ligand Interaction ◽  
Energy Simulations ◽  
Hiv 1

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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