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Accessory mutations balance the marginal stability of the HIV-1 protease in drug resistance.
Proteins: Structure, Function, and Bioinformatics ( IF 3.2 ) Pub Date : 2019-10-21 , DOI: 10.1002/prot.25826
Thomas R Weikl 1 , Bahram Hemmateenejad 1, 2
Affiliation  

The HIV-1 protease is a major target of inhibitor drugs in AIDS therapies. The therapies are impaired by mutations of the HIV-1 protease that can lead to resistance to protease inhibitors. These mutations are classified into major mutations, which usually occur first and clearly reduce the susceptibility to protease inhibitors, and minor, accessory mutations that occur later and individually do not substantially affect the susceptibility to inhibitors. Major mutations are predominantly located in the active site of the HIV-1 protease and can directly interfere with inhibitor binding. Minor mutations, in contrast, are typically located distal to the active site. A central question is how these distal mutations contribute to resistance development. In this article, we present a systematic computational investigation of stability changes caused by major and minor mutations of the HIV-1 protease. As most small single-domain proteins, the HIV-1 protease is only marginally stable. Mutations that destabilize the folded, active state of the protease therefore can shift the conformational equilibrium towards the unfolded, inactive state. We find that the most frequent major mutations destabilize the HIV-1 protease, whereas roughly half of the frequent minor mutations are stabilizing. An analysis of protease sequences from patients in treatment indicates that the stabilizing minor mutations are frequently correlated with destabilizing major mutations, and that highly resistant HIV-1 proteases exhibit significant fractions of stabilizing mutations. Our results thus indicate a central role of minor mutations in balancing the marginal stability of the protease against the destabilization induced by the most frequent major mutations.

中文翻译:

附件突变平衡了HIV-1蛋白酶在耐药性方面的边缘稳定性。

HIV-1蛋白酶是AIDS治疗中抑制剂药物的主要靶标。HIV-1蛋白酶的突变会削弱治疗效果,这种突变可能导致对蛋白酶抑制剂的耐药性。这些突变被分类为主要突变,通常首先发生并明显降低了对蛋白酶抑制剂的敏感性,而次要的次要突变则在以后发生并个别地基本上不影响对抑制剂的敏感性。主要突变主要位于HIV-1蛋白酶的活性位点,可以直接干扰抑制剂的结合。相反,较小的突变通常位于活性位点的远端。一个中心问题是这些远端突变如何促进耐药性的发展。在本文中,我们目前对由HIV-1蛋白酶的主要和次要突变引起的稳定性变化进行系统的计算研究。作为大多数小的单结构域蛋白,HIV-1蛋白酶只是勉强稳定的。因此,使蛋白酶的折叠的活性状态不稳定的突变可将构象平衡移向未折叠的无活性状态。我们发现,最常见的主要突变使HIV-1蛋白酶不稳定,而大约一半的常见次要突变却稳定下来。对来自接受治疗的患者的蛋白酶序列的分析表明,稳定的次要突变通常与不稳定的主要突变相关,并且高抗性的HIV-1蛋白酶显示出稳定突变的重要部分。
更新日期:2020-01-24
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