Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease.
Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease.
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DOI：
10.1021/jacsau.3c00185
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发表时间：
2023-06-26
期刊：
影响因子：
8
通讯作者：
Duarte, Fernanda
中科院分区：
文献类型：
--
作者：
Chan, H T Henry;Oliveira, A Sofia F;Schofield, Christopher J;Mulholland, Adrian J;Duarte, Fernanda
SARS-CoV-2主要蛋白酶（Mpro）通过催化病毒多聚蛋白在特定位点的水解在冠状病毒生命周期中发挥重要作用。Mpro是nirmatrelvir等药物的靶点，尽管已经出现了威胁药物疗效的耐药突变体。尽管它的重要性，问题仍然存在于Mpro如何结合其底物的机制。在这里，我们应用动态非平衡分子动力学（D-NEMD）模拟来评估的Mpro的存在和不存在的基板的结构和动力学响应。结果突出了Mpro二聚体亚基之间的通信，并确定了网络，包括一些远离活性位点的网络，这些网络将活性位点与已知的变构抑制位点联系起来，或者与Nirmatrelvir耐药相关。它们意味着一些突变通过改变Mpro的变构行为来实现抗性。更一般地，结果显示了D-NEMD技术用于鉴定功能相关的变构位点和网络的实用性，包括与抗性相关的那些。
The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.