Hydrophobic Sliding: A Possible Mechanism for Drug Resistance in Human Immunodeficiency Virus Type 1 Protease

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.

Cellulose microfibril crystallinity is reduced by mutating C-terminal transmembrane region residues CESA1 A903V and CESA3 T942I of cellulose synthase

“…Supporting this postulate, live-cell imaging studies revealed clearance of YFP∷ CESA6 from the PM after quinoxyphen treatment, although resistance was conferred by CESA1 A903V . Precedence for the observed resistance mechanism whereby drug-binding affinity is displaced via mutation of residues in a transmembrane spanning region has been observed in the case of hydrophobic sliding for drug resistance in HIV-type 1 protease (39).…”

The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways

“…The lower turnover rates of the AE variants could be a direct result of the reduced flexibility of the flap hinge (residues 33 to 39) and core regions (residues 16 to 22) of the protein. Molecular dynamics studies have revealed that hydrophobic sliding of the core region facilitates substrate binding through the opening of the active site (9). The unique hydrogen bonds observed between the flap hinge and the core in the AE variants alter movement of the core, thus impacting the ability of the active site to open up for substrate binding and product release.…”

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

“…Slow exchange is expected here due to low solvent accessibility and a complex network of interactions around the active-site core. The flap tips (residues at positions [49][50][51][52][53] are the regions of the proteases that display the fastest deuterium incorporation. The flaps are completely solvent-exposed and highly mobile.…”

“…An MD simulation study identified hydrophobic residues whose side chains were buried for the majority of the simulation [51]. These 19 residues per monomer are referred to as the hydrophobic core of the protease (Fig.…”

“…Polymorphic sites of the subtype B protease (PDB ID: 2PC0) [13] and the C-SA protease (PDB ID: 3U71) [37]. The flexible flaps of the protease (residues at positions [46][47][48][49][50][51][52][53][54] are coloured cyan. The fulcrum region (residues at positions 10-23), hinge region (residues at positions 35-42 and 57-61) and cantilever region (residues at positions 62-78) are implicated in flap opening.…”