Proteins, Vol. 43, p. 365-372, (2001)
Molecular Dynamics Studies on HIV-1 Protease: Drug Resistance and
Folding Pathways
Fabio Cecconi, Cristian Micheletti, Paolo Carloni and Amos Maritan
Link to online article.
ABSTRACT Drug resistance to HIV-1 Protease involves 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.