Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV‑1 Protease

A human immunodeficiency virus-1
(HIV-1) protease is a homodimeric
aspartic protease essential for the replication of HIV. The HIV-1
protease is a target protein in drug discovery for antiretroviral
therapy, and various inhibitor molecules of transition state analogues
have been developed. However, serious drug-resistant mutants have
emerged. For understanding the molecular mechanism of the drug resistance,
an accurate examination of the impacts of the mutations on ligand
binding and enzymatic activity is necessary. Here, we present a molecular
simulation study on the ligand binding of indinavir, a potent transition
state analogue inhibitor, to the wild-type protein and a V82T/I84V
drug-resistant mutant of the HIV-1 protease. We employed a hybrid
ab initio quantum mechanical/molecular mechanical (QM/MM) free-energy
optimization technique which combines a highly accurate QM description
of the ligand molecule and its interaction with statistically ample
conformational sampling of the MM protein environment by long-time
molecular dynamics simulations. Through the free-energy calculations
of protonation states of catalytic groups at the binding pocket and
of the ligand-binding affinity changes upon the mutations, we successfully
reproduced the experimentally observed significant reduction of the
binding affinity upon the drug-resistant mutations and elucidated
the underlying molecular mechanism. The present study opens the way
for understanding the molecular mechanism of drug resistance through
the direct quantitative comparison of ligand binding and enzymatic
reaction with the same accuracy.