Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease.
Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues slide by each other, exchanging one hydrophobic van der Waal contact for another, with little energy penalty, while maintaining many structurally important hydrogen bonds. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these residues in HIV-1 protease would alter the packing of the hydrophobic core, affecting the conformational flexibility of the protease. Therefore these residues impact the dynamic balance between processing substrates and binding inhibitors, and thus contribute to drug resistance.
Foulkes-Murzycki
Jennifer E
JE
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Scott
Walter Robert Peter
WR
Schiffer
Celia A
CA
D000596:Amino Acids / Q000737:chemistry; D024882:Drug Resistance, Viral / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D009154:Mutation; D011487:Protein Conformation
D000596:Amino Acids; D017320:HIV Protease Inhibitors; D016333:HIV Protease