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Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors.
The Journal of Chemical Physics ( IF 4.4 ) Pub Date : 2020-09-15 , DOI: 10.1063/5.0020458
Jack A Henderson 1 , Neha Verma 1 , Robert C Harris 1 , Ruibin Liu 1 , Jana Shen 1
Affiliation  

Broad-spectrum antiviral drugs are urgently needed to stop the Coronavirus Disease 2019 pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused the previous outbreaks. The papain-like protease (PLpro) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro is rich in cysteines and histidines, and their protonation/deprotonation modulates catalysis and conformational plasticity. Here, we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV and MERS-CoV PLpros using the recently developed graphical processing unit (GPU)-accelerated implicit-solvent continuous constant pH molecular dynamics method with a new asynchronous replica-exchange scheme, which allows computation on a single GPU card. The calculated pKa’s support the catalytic roles of the Cys–His–Asp triad. We also found that several residues can switch protonation states at physiological pH among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro. Simulations revealed that the BL2 can open and close depending on the protonation state of C271/270, consistent with the most recent crystal structure evidence. Interestingly, despite the lack of an analogous cysteine, BL2 in MERS-CoV PLpro is also very flexible, challenging a current hypothesis. These findings are supported by the all-atom fixed-charge simulations and provide a starting point for more detailed studies to assist the structure-based design of broad-spectrum inhibitors against CoV PLpros.

中文翻译:

评估SARS和MERS冠状病毒木瓜蛋白酶样蛋白酶的质子偶联构象动力学:对设计广谱抗病毒抑制剂的意义。

迫切需要广谱抗病毒药物来阻止2019年冠状病毒病大流行并预防未来大流行。新型严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)与SARS-CoV和中东呼吸系统综合症冠状病毒(MERS-CoV)有关,它们引起了先前的暴发。木瓜蛋白酶样蛋白酶(PLpro)由于其在病毒生命周期中的重要作用而成为有吸引力的药物靶标。作为半胱氨酸蛋白酶,PLpro富含半胱氨酸和组氨酸,其质子化/去质子化可调节催化作用和构象可塑性。在这里,我们报告pK a使用最近开发的图形处理单元(GPU)加速的隐式溶剂连续恒定pH分子动力学方法和SARS-CoV-2和MERS-CoV PLpros的SARS-CoV-2质子偶联构象动力学的计算和评估新的异步副本交换方案,该方案允许在单个GPU卡上进行计算。计算出的pK a支持Cys-His-Asp三联体的催化作用。我们还发现,几个残基可以在生理pH值下切换质子化状态,其中C270 / 271位于SARS-CoV-2 / CoV PLpro的柔性封闭环2(BL2)上。模拟显示BL2可以根据C271 / 270的质子化状态打开和关闭,这与最新的晶体结构证据一致。有趣的是,尽管缺少类似的半胱氨酸,MERS-CoV PLpro中的BL2也非常灵活,挑战了当前的假设。这些发现得到全原子固定电荷模拟的支持,并为更详细的研究提供了起点,以协助针对CoV PLpros的广谱抑制剂的基于结构的设计。
更新日期:2020-09-21
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