Drug resistance to HIV-1 protease involves the accumulation of multiple
mutations in the protein. We investigate the role of these mutations by
using molecular dynamics simulations that exploit the influence of the
native-state topology in the folding process. Our calculations show that
sites contributing to phenotypic resistance of FDA-approved drugs are
among the most sensitive positions for the stability of partially folded
states and should play a relevant role in the folding process.
Furthermore, associations between amino acid sites mutating under drug
treatment are shown to be statistically correlated. The striking
correlation between clinical data and our calculations suggest a novel
approach to the design of drugs tailored to bind regions crucial not
only for protein function, but for folding as well.
