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.
|Titolo:||Molecular dynamics studies on HIV-1 protease: drug resistance and folding pathways,|
|Autori:||Cecconi F; Micheletti C; Carloni P; Maritan A|
|Data di pubblicazione:||2001|
|Digital Object Identifier (DOI):||10.1002/prot.1049.abs|
|Appare nelle tipologie:||1.1 Journal article|