title: In silico prediction of mutant HIV-1 proteases cleaving a target sequence.
abstract: HIV-1 protease represents an appealing system for directed enzyme re-design, since it has various different endogenous targets, a relatively simple structure and it is well studied. Recently Chaudhury and Gray (Structure (2009) 17: 1636-1648) published a computational algorithm to discern the specificity determining residues of HIV-1 protease. In this paper we present two computational tools aimed at re-designing HIV-1 protease, derived from the algorithm of Chaudhuri and Gray. First, we present an energy-only based methodology to discriminate cleavable and non cleavable peptides for HIV-1 proteases, both wild type and mutant. Secondly, we show an algorithm we developed to predict mutant HIV-1 proteases capable of cleaving a new target substrate peptide, different from the natural targets of HIV-1 protease. The obtained in silico mutant enzymes were analyzed in terms of cleavability and specificity towards the target peptide using the energy-only methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence.
authors.affiliation: Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Jensen
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Willemoës
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Winther
authors.affiliation: Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Luca
authors.initials: L
authors.lastname: De Vico
mesh_terms: D000465:Algorithms; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D059748:Proteolysis
chemical_list: D017320:HIV Protease Inhibitors; D010455:Peptides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1