In silico prediction of mutant HIV-1 proteases cleaving a target sequence

PLoS One. 2014 May 5;9(5):e95833. doi: 10.1371/journal.pone.0095833. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemistry*
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Models, Molecular*
  • Mutation*
  • Peptides / chemistry*
  • Proteolysis*

Substances

  • HIV Protease Inhibitors
  • Peptides
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1

Grants and funding

Funds were provided by the Danish Research Council for Technology and Production Sciences (FTP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.