Structure-based prediction of potential binding and nonbinding peptides to HIV-1 protease

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Binding Sites; Computer Simulation; Electrochemistry; Energy Transfer; Enzyme Activation; Enzyme Stability; Gene Products, gag; Gene Products, pol; HIV Protease; Macromolecular Substances; *Models, Chemical; *Models, Molecular; Motion; Polyproteins; Protein Binding; Structure-Activity Relationship; Substrate Specificity


Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health


HIV-1 protease is a major drug target against AIDS as it permits viral maturation by processing the gag and pol polyproteins of the virus. The cleavage sites in these polyproteins do not have obvious sequence homology or a binding motif and the specificity of the protease is not easily determined. We used various threading approaches, together with the crystal structures of substrate complexes which served as template structures, to study the substrate specificity of HIV-1 protease with the aim of obtaining a better differentiation between binding and nonbinding sequences. The predictions from threading improved when distance-dependent interaction energy functions were used instead of contact matrices. To rank the peptides and properly account for the peptide's conformation in the total energy, the results from using short-range potentials on multiple template structures were averaged. Finally, a dynamic threading approach is introduced which is potentially useful for cases when there is only one template structure available. The conformational energy of the peptide-especially the term accounting for the side chains-was found to be important in differentiating between binding and nonbinding sequences. Hence, the substrate specificity, and thus the ability of the virus to mature, is affected by the compatibility of the substrate peptide to fit within the limited conformational space of the active site groove.

DOI of Published Version



Biophys J. 2003 Aug;85(2):853-63. Link to article on publisher's site

Journal/Book/Conference Title

Biophysical journal

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Link to Article in PubMed

PubMed ID