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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 21, Number 12
BKCSDE 21(12)
December 20, 2000 

Binding Free Energy Simulations of the HIV-1 Protease and Hydroxyethylene Isostere Inhibitors
Youngdo Won
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 ther-modynamic cycle, which reduces the free energy difference of the binding interactions into that of the alchem-ical 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 differ-ence. The protonation state of the catalytic aspartic acid residues is also investigated through the free energy simulations.
1207 - 1212
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