Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Binding Free Energy Simulations of the HIV-1 Protease and Hydroxyethylene Isostere Inhibitors

  • Published : 20001200
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Abstract

The free energy simulation technique is used to evaluate the relative binding affinity of a set of hydroxyethylene isostere inhibitors of the HIV-1 protease. The binding reactions and an alchemical mutation construct the thermodynamic cycle, which reduces the free energy difference of the binding interactions into that of the alchemical processes. In the alchemical process, a methyl group is mutated into a hydrogen atom. Albeit the change is a small perturbation to the inhibitor-protease complex, it results in 25 fold difference in the binding constants. The simulation reproduces the experimentally measured binding affinities within 2% of the free energy difference. The protonation state of the catalytic aspartic acid residues is also investigated through the free energy simulations.

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