Molecular dynamics studies on HIV-1 protease drug resistance and folding pathways

Drug resistance to HIV-1 protease involves the accumulation of multiple mut ations in the protein. We investigate the role of these mutations by using molecular dynamics simulations that exploit the influence of the native-sta te topology in the folding process. Our calculations show that sites contri buting to phenotypic resistance of FDA-approved drugs are among the most se nsitive positions for the stability of partially folded states and should p lay a relevant role in the folding process. Furthermore, associations betwe en amino acid sites mutating under drug treatment are shown to be statistic ally correlated. The striking correlation between clinical data and our cal culations suggest a novel approach to the design of drugs tailored to bind regions crucial not only for protein function, but for folding as well. Pro teins 2001;43:365-372. (C) 2001 Wiley-Liss, Inc.