Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2014 May 5;9(5):e95833. doi: 10.1371/journal.pone.0095833. eCollection 2014.
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.
HIV-1 蛋白酶是定向酶重新设计的有吸引力的系统，因为它具有各种不同的内源性靶标、相对简单的结构和良好的研究基础。最近，Chaudhury 和 Gray（结构（2009）17：1636-1648）发表了一种计算算法，用于辨别 HIV-1 蛋白酶的特异性决定残基。在本文中，我们提出了两种源自 Chaudhury 和 Gray 算法的计算工具，旨在重新设计 HIV-1 蛋白酶。首先，我们提出了一种仅基于能量的方法来区分 HIV-1 蛋白酶野生型和突变型的可切割和不可切割肽。其次，我们展示了一种我们开发的算法，用于预测能够切割新靶标肽的突变 HIV-1 蛋白酶，该肽不同于 HIV-1 蛋白酶的天然靶标。使用仅基于能量的方法，我们根据可切割性和对靶肽的特异性对获得的计算机突变酶进行了分析。我们发现两种突变蛋白酶是针对靶序列的特异性和可切割性的最佳候选者。
