Role of allosteric mutations in HIV-1 protease drug resistance: Useful Insights for Rational Drug Design

Tidsperiod: 2017-01-01 till 2018-12-31

Projektledare: Jens Carlsson

Finansiär: Vetenskapsrådet

Bidragstyp: Stöd till forskningsmiljö

Budget: 601 020 SEK

Allosteric regulation is fundamental to protein function. HIV-1 protease from drug-treated patients acquires multiple allosteric mutations that resist drugs profoundly with little impact on enzymatic activity. The mechanism of allosteric regulation of these mutations to drug binding and protease activity remains elusive even today. Inspired by the recent success of network theory in precise elucidation of allosteric signaling in proteins and protein-effector complexes, here we propose to probe the effects of allosteric mutations in HIV-1 protease’s drug resistance and unhindered function by means of residue- and community-based networks. The networks are proposed to make more accurate by explicit inclusion of the dynamical information of the protein from the molecular dynamics (MD) simulation results of its free and drug-bound states and also in presence and absence of the mutations. At the end, with predicted propensity of conservation of each protein residue and their optimal (and suboptimal) paths to the active site and flaps, the study is expected to pave way for designing new-generation HIV-1 protease allosteric inhibitors that could make greater contacts with conserved residues located away from the active site.