Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease
Department of Biochemistry and Molecular Pharmacology
Amino Acids; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; Hydrogen Bonding; Hydrophobicity; Mutation; Protein Conformation
Life Sciences | Medicine and Health Sciences
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.
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Citation: Structure. 2007 Feb;15(2):225-33. Link to article on publisher's site