Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, Illinois 60637, United States.
Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, United States.
J Am Chem Soc. 2021 Nov 17;143(45):19137-19148. doi: 10.1021/jacs.1c08922. Epub 2021 Nov 5.
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.
人类免疫缺陷病毒 1 型（HIV-1）的组装和成熟需要对 Gag 多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，它们组装成六螺旋束（6HB）。贝伐单抗（BVM）是首个上市的成熟抑制剂药物，靶向 6HB 并阻碍蛋白水解切割，但它的作用机制及其相关的突变病毒逃逸机制仍不清楚。在这里，我们采用广泛的分子动力学（MD）模拟和自由能计算来定量研究结构-活性关系，比较了野生型和突变型病毒在存在和不存在 BVM 和肌醇六磷酸（IP6）的情况下的结构-活性关系，IP6 是一种组装辅助因子。我们的分析表明，BVM 的功效与 6HB 中的六倍对称性的保持直接相关，6HB 作为结构状态的集合存在。我们确定了两种主要的逃逸机制，这两种机制都导致对称性丧失，从而促进螺旋解卷，以帮助蛋白酶进入。我们的研究结果还突出了可以针对提高抑制剂活性的特定相互作用，并支持使用 MD 模拟进行未来的抑制剂设计。
