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

TY - JOUR

T1 - In Silico prediction of mutant HIV-1 proteases cleaving a target sequence

AU - Jensen, Jan Halborg

AU - Willemoës, Martin

AU - Winther, Jakob R.

AU - De Vico, Luca

N1 - OA

PY - 2014/5/5

Y1 - 2014/5/5

N2 - 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 energyonly methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence.

AB - 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 energyonly methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence.

U2 - 10.1371/journal.pone.0095833

DO - 10.1371/journal.pone.0095833

M3 - Journal article

C2 - 24796579

SN - 1932-6203

VL - 9

JO - P L o S One

JF - P L o S One

IS - 5

M1 - 5

ER -