Tekpinar Mustafa, Yildirim Ahmet
Unit of Structural Dynamics of Biological Macromolecules, Pasteur Institute, UMR 3528 CNRS, Paris, France.
Department of Physics, Siirt University, Siirt, Turkey.
J Biomol Struct Dyn. 2022 Sep;40(14):6243-6254. doi: 10.1080/07391102.2021.1880481. Epub 2021 Feb 2.
SARS-CoV-2 main protease is one of the major targets in drug development efforts against Covid-19. Even though several structures were reported to date, its dynamics is not understood well. In particular, impact of dimerization and ligand binding on the dynamics is an important issue to investigate. In this study, we performed molecular dynamics simulations of SARS-CoV and SARS-CoV-2 main proteases to investigate influence of dimerization on the dynamics by modeling monomeric and dimeric apo and holo forms. The dimerization causes an organization of the interdomain dynamics as well as some local structural changes. Moreover, we investigated impact of a peptide mimetic (N3) on the dynamics of SARS-CoV and SARS-CoV-2 Mpro. The ligand binding to the dimeric forms causes some key local changes at the dimer interface and it causes an allosteric interaction between the active sites of two protomers. Our results support the idea that only one protomer is active on SARS-CoV-2 due to this allosteric interaction. Additionally, we analyzed the molecular dynamics trajectories from graph theoretical perspective and found that the most influential residues - as measured by eigenvector centrality - are a group of residues in active site and dimeric interface of the protease. This study may form a bridge between what we know about the dynamics of SARS-CoV and SARS-CoV-2 Mpro. We think that enlightening allosteric communication of the active sites and the role of dimerization in SARS-CoV-2 Mpro can contribute to development of novel drugs against this global health problem as well as other similar proteases. Communicated by Ramaswamy H. Sarma.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶是抗2019冠状病毒病（Covid-19）药物研发的主要靶点之一。尽管迄今为止已报道了几种结构，但其动力学仍未得到很好的理解。特别是，二聚化和配体结合对动力学的影响是一个重要的研究问题。在本研究中，我们对SARS-CoV和SARS-CoV-2主要蛋白酶进行了分子动力学模拟，通过构建单体和二聚体的无配体和有配体形式来研究二聚化对动力学的影响。二聚化导致结构域间动力学的组织以及一些局部结构变化。此外，我们研究了一种肽模拟物（N3）对SARS-CoV和SARS-CoV-2 Mpro动力学的影响。配体与二聚体形式的结合在二聚体界面引起一些关键的局部变化，并在两个原体的活性位点之间引起变构相互作用。我们的结果支持这样一种观点，即由于这种变构相互作用，SARS-CoV-2上只有一个原体是有活性的。此外，我们从图论的角度分析了分子动力学轨迹，发现最具影响力的残基（以特征向量中心性衡量）是蛋白酶活性位点和二聚体界面中的一组残基。这项研究可能在我们对SARS-CoV和SARS-CoV-2 Mpro动力学的了解之间架起一座桥梁。我们认为，阐明SARS-CoV-2 Mpro活性位点的变构通讯以及二聚化的作用，有助于开发针对这一全球健康问题以及其他类似蛋白酶的新型药物。由拉马斯瓦米·H·萨尔马传达。
