Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.
Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.
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DOI：
10.1021/acs.jctc.7b00601
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发表时间：
2017-11-14
影响因子：
5.5
通讯作者：
Schiffer CA
中科院分区：
文献类型：
--
作者：
Ragland DA;Whitfield TW;Lee SK;Swanstrom R;Zeldovich KB;Kurt-Yilmaz N;Schiffer CA
HIV-1蛋白酶负责裂解病毒基因组中Gag和Gag-Pro-Pol多蛋白中的12个非同源位点。在蛋白酶抑制的选择性压力下，病毒在(初级)活性部位内和(次级)活性部位外进化突变，允许蛋白酶在处理底物的同时对抗抑制。主要的蛋白水解酶突变直接阻碍抑制物结合，而次要突变被认为是弥补适应性损失的辅助突变。然而，继发性突变在导致耐药性方面的作用在很大程度上仍然是一个悬而未决的话题。我们先前已经证明，活性位点远端的突变能够通过蛋白质的内部氢键网络扰乱达鲁那韦(DRV)的结合。在这项研究中，我们表明，活性部位远端的突变，无论背景如何，都可以在耐药中发挥相互依赖的作用。应用本征值分解对来自15个不同HIV-1蛋白酶变体的一系列分子动力学模拟中的氢键和van der Waals相互作用进行收集，我们确定了蛋白酶中氨基酸取代导致与DRV和/或蛋白酶本身的氢键网络的非键相互作用的扰动的位置。虽然已知主要突变会导致HIV-1蛋白酶的耐药性，但这些发现描绘了辅助突变对耐药性的重大贡献。确定对耐药性有最大影响的蛋白水解酶中的可变位置可能有助于未来基于结构的抑制剂设计。
HIV-1 protease is responsible for the cleavage of 12 non-homologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the virus evolves mutations within (primary) and outside of (secondary) the active site allowing the protease to process substrates while simultaneously countering inhibition. The primary protease mutations impede inhibitor binding directly, while the secondary mutations are considered accessory mutations that compensate for a loss in fitness. However, the role of secondary mutations in conferring drug resistance remains a largely unresolved topic. We have shown previously that mutations distal to the active site are able to perturb binding of darunavir (DRV) via the protein’s internal hydrogen-bonding network. In this study we show that mutations distal to the active site, regardless of context, can play an interdependent role in drug resistance. Applying eigenvalue decomposition to collections of hydrogen bonding and van der Waals interactions from a series of molecular dynamics simulations of 15 diverse HIV-1 protease variants, we identify sites in the protease where amino acid substitutions lead to perturbations in non-bonded interactions with DRV and/or the hydrogen-bonding network of the protease itself. While primary mutations are known to drive resistance in HIV-1 protease, these findings delineate the significant contributions of accessory mutations to resistance. Identifying the variable positions in the protease that have the greatest impact on drug resistance may aid in future structure-based design of inhibitors.
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