Drug resistance is a severe problem in HIV treatment. HIV protease is a common target for the design of new drugs for treating HIV infection. Previous studies have shown that the crystallographic structures of the HIV-2 protease (PR2) in bound and unbound forms exhibit structural asymmetry that is important for ligand recognition and binding. Here, we investigated the effects of resistance mutations on the structural asymmetry of PR2. Due to the lack of structural data on PR2 mutants, the 3D structures of 30 PR2 mutants of interest have been modeled using an in silico protocol. Structural asymmetry analysis was carried out with an in-house structural-alphabet-based approach. The systematic comparison of the asymmetry of the wild-type structure and a large number of mutants highlighted crucial residues for PR2 structure and function. In addition, our results revealed structural changes induced by PR2 flexibility or resistance mutations. The analysis of the highlighted structural changes showed that some mutations alter protein stability or inhibitor binding. This work consists of a structural analysis of the impact of a large number of PR2 resistant mutants based on modeled structures. It suggests three possible resistance mechanisms of PR2, in which structural changes induced by resistance mutations lead to modifications in the dimerization interface, ligand recognition or inhibitor binding.

中文翻译：

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耐药性突变对HIV-2蛋白酶结构不对称的影响。

耐药性是HIV治疗中的严重问题。HIV蛋白酶是设计用于治疗HIV感染的新药物的共同目标。先前的研究表明，结合和未结合形式的HIV-2蛋白酶（PR2）的晶体结构显示出对配体识别和结合很重要的结构不对称性。在这里，我们调查了抗性突变对PR2的结构不对称的影响。由于缺少PR2突变体的结构数据，已使用计算机模拟方案对30个感兴趣的PR2突变体的3D结构进行了建模。使用基于内部结构字母的方法进行结构不对称分析。对野生型结构和大量突变体的不对称性的系统比较突出了PR2结构和功能的关键残基。此外，我们的结果揭示了PR2柔韧性或抗性突变引起的结构变化。对突出显示的结构变化的分析表明，某些突变会改变蛋白质的稳定性或抑制剂的结合。这项工作包括基于建模的结构对大量PR2抗性突变体的影响进行结构分析。它提出了PR2的三种可能的抗性机制，其中由抗性突变诱导的结构变化导致二聚化界面，配体识别或抑制剂结合的修饰。这项工作包括基于建模的结构对大量PR2抗性突变体的影响进行结构分析。它提出了PR2的三种可能的抗性机制，其中由抗性突变诱导的结构变化导致二聚化界面，配体识别或抑制剂结合的修饰。这项工作包括基于建模的结构对大量PR2抗性突变体的影响进行结构分析。它提出了PR2的三种可能的抗性机制，其中由抗性突变诱导的结构变化导致二聚化界面，配体识别或抑制剂结合的修饰。