Title
Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2007-02-13
Document Type
Article
Subjects
Amino Acids; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; Hydrogen Bonding; Hydrophobicity; Mutation; Protein Conformation
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
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.
DOI of Published Version
10.1016/j.str.2007.01.006
Source
Structure. 2007 Feb;15(2):225-33. Link to article on publisher's site
Journal/Book/Conference Title
Structure (London, England : 1993)
Related Resources
PubMed ID
17292840
Repository Citation
Foulkes-Murzycki JE, Scott WR, Schiffer CA. (2007). Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease. Open Access Publications by UMass Chan Authors. https://doi.org/10.1016/j.str.2007.01.006. Retrieved from https://escholarship.umassmed.edu/oapubs/1365