Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Amino Acid Sequence; Conserved Sequence; Crystallography, X-Ray; Drug Resistance, Viral; HIV Protease; HIV-1; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Molecular Sequence Data; Mutation; Substrate Specificity


Molecular Biology | Virology


Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate envelope, because these regions are crucial for drug binding but not for substrate recognition. We extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. We simulated the molecular dynamics of seven PR-substrate complexes to estimate the conformational flexibility of the bound substrates. Interdependence of substrate-protease interactions might compensate for variations in cleavage-site sequences and explain how a diverse set of sequences are recognized as substrates by the same enzyme. This diversity might be essential for regulating sequential processing of substrates. We define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance.

DOI of Published Version



J Mol Biol. 2011 Jul 22;410(4):726-44. Link to article on publisher's site

Journal/Book/Conference Title

Journal of molecular biology


Co-author Aysegul Ozen is a student in the Biochemistry & Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

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PubMed ID