Preservation of HIV-1 Gag Helical Bundle Symmetry by Bevirimat Is Central to Maturation Inhibition.
Preservation of HIV-1 Gag Helical Bundle Symmetry by Bevirimat Is Central to Maturation Inhibition.
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DOI：
10.1021/jacs.1c08922
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发表时间：
2021-11-17
影响因子：
15
通讯作者：
Voth GA
中科院分区：
文献类型：
--
作者：
Pak AJ;Purdy MD;Yeager M;Voth GA
人类免疫缺陷病毒1型（HIV - 1）的组装和成熟需要对Gag多聚蛋白进行蛋白水解切割。限速步骤位于衣壳蛋白CA和间隔肽1之间的连接处，此处组装成一个六螺旋束（6HB）。贝韦立马特（BVM）是首个成熟抑制剂类药物，它以6HB为靶点并阻碍蛋白水解切割，然而其活性的分子机制以及相关的突变病毒逃逸机制仍不清楚。在此，我们运用大量分子动力学（MD）模拟和自由能计算来定量研究分子结构 - 活性关系，比较在有和没有BVM以及肌醇六磷酸（IP6，一种组装辅因子）存在的情况下野生型和突变病毒。我们的分析表明，BVM的功效与6HB中6重对称性的保持直接相关，6HB以一系列结构状态存在。我们确定了两种主要的逃逸机制，并且这两种机制都导致对称性丧失，从而有利于螺旋展开以帮助蛋白酶接近。我们的研究结果还强调了可作为提高抑制剂活性靶点的特定相互作用，并支持将分子动力学模拟用于未来抑制剂的设计。
The assembly and maturation of human immunodeficiency virus type 1 (HIV-1) require proteolytic cleavage of the Gag polyprotein. The rate-limiting step resides at the junction between the capsid protein CA and spacer peptide 1, which assembles as a six-helix bundle (6HB). Bevirimat (BVM), the first-in-class maturation inhibitor drug, targets the 6HB and impedes proteolytic cleavage, yet the molecular mechanisms of its activity, and relatedly, the escape mechanisms of mutant viruses, remain unclear. Here, we employed extensive molecular dynamics (MD) simulations and free energy calculations to quantitatively investigate molecular structure–activity relationships, comparing wild-type and mutant viruses in the presence and absence of BVM and inositol hexakisphosphate (IP6), an assembly cofactor. Our analysis shows that the efficacy of BVM is directly correlated with preservation of 6-fold symmetry in the 6HB, which exists as an ensemble of structural states. We identified two primary escape mechanisms, and both lead to loss of symmetry, thereby facilitating helix uncoiling to aid access of protease. Our findings also highlight specific interactions that can be targeted for improved inhibitor activity and support the use of MD simulations for future inhibitor design.
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DOI：
10.1073/pnas.1917755117
发表时间：
2020-05-12
影响因子：
11.1
作者：
Gupta, Sebanti;Louis, John M.;Tycko, Robert
通讯作者：
Tycko, Robert
影响因子：
4.4
作者：
Bussi, Giovanni;Zykova-Timan, Tatyana;Parrinello, Michele
通讯作者：
Parrinello, Michele
影响因子：
5.4
作者：
Adamson, Catherine S.;Ablan, Sherimay D.;Freed, Eric O.
通讯作者：
Freed, Eric O.
影响因子：
3.4
作者：
McGibbon, Robert T.;Beauchamp, Kyle A.;Pande, Vijay S.
通讯作者：
Pande, Vijay S.
影响因子：
64.8
作者：
Dick RA;Zadrozny KK;Xu C;Schur FKM;Lyddon TD;Ricana CL;Wagner JM;Perilla JR;Ganser-Pornillos BK;Johnson MC;Pornillos O;Vogt VM
通讯作者：
Vogt VM