Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.
Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.
复制标题
DOI：
10.1186/1471-2164-15-s7-s5
复制
发表时间：
2014
期刊：
影响因子：
4.4
通讯作者：
Batista PR
中科院分区：
文献类型：
--
作者：
Costa MG;Benetti-Barbosa TG;Desdouits N;Blondel A;Bisch PM;Pascutti PG;Batista PR
在过去的几十年里，已经收集了大量关于HIV-1蛋白酶（PR）的结构知识。值得注意的是，大多数研究集中在B亚型，这在发达国家的流行率最高。因此，目前可用的抗HIV药物靶向该亚型，对相应的患者具有相当大的益处。然而，在发展中国家，有各种各样的HIV-1亚型携带与药物敏感性降低相关的PR多态性。非活性位点突变M36 I是最常见的多态性，被认为是非B亚型标记。然而，这种取代对PR结构和与天然底物的相互作用的结构影响仍然很少记录。在这里，我们使用分子动力学模拟研究的作用，这种多态性的相互作用PR与其天然裂解位点的基板。MMPB/SA计算的自由能分析表明，M36 I-PR对大多数底物的亲和力降低。唯一的例外是RT-RH，具有相同的亲和力，和RH-IN，其中一个增加的亲和力被发现。此外，分子模拟表明，与其他肽，RH-IN诱导更大的结构波动的野生型酶比在M36 I变体。通过多种方法和分析，我们确定了与M36 I变体结合亲和力变化相关的结构和动力学决定因素。这种突变影响PR及其复合底物的灵活性。观察到的M36 I的影响表明，与其他非B亚型多态性的组合可能会对与12个已知切割位点的相互作用产生重大影响，这将影响病毒粒子的成熟。
Over the last decades, a vast structural knowledge has been gathered on the HIV-1 protease (PR). Noticeably, most of the studies focused the B-subtype, which has the highest prevalence in developed countries. Accordingly, currently available anti-HIV drugs target this subtype, with considerable benefits for the corresponding patients. However, in developing countries, there is a wide variety of HIV-1 subtypes carrying PR polymorphisms related to reduced drug susceptibility. The non-active site mutation, M36I, is the most frequent polymorphism, and is considered as a non-B subtype marker. Yet, the structural impact of this substitution on the PR structure and on the interaction with natural substrates remains poorly documented. Herein, we used molecular dynamics simulations to investigate the role of this polymorphism on the interaction of PR with six of its natural cleavage-sites substrates. Free energy analyses by MMPB/SA calculations showed an affinity decrease of M36I-PR for the majority of its substrates. The only exceptions were the RT-RH, with equivalent affinity, and the RH-IN, for which an increased affinity was found. Furthermore, molecular simulations suggest that, unlike other peptides, RH-IN induced larger structural fluctuations in the wild-type enzyme than in the M36I variant. With multiple approaches and analyses we identified structural and dynamical determinants associated with the changes found in the binding affinity of the M36I variant. This mutation influences the flexibility of both PR and its complexed substrate. The observed impact of M36I, suggest that combination with other non-B subtype polymorphisms, could lead to major effects on the interaction with the 12 known cleavage sites, which should impact the virion maturation.