title: Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease.
abstract: Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive. Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Foulkes-Murzycki
authors.forename: Christina
authors.initials: C
authors.lastname: Rosi
authors.forename: Nese
authors.initials: N
authors.lastname: Kurt Yilmaz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D002151:Calorimetry; D024882:Drug Resistance, Viral / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D013816:Thermodynamics
chemical_list: D016333:HIV Protease