Ramos-Guzmán Carlos A, Ruiz-Pernía J Javier, Tuñón Iñaki
Departamento de Química Física, Universidad de Valencia, 46100 Burjassot, Spain.
ACS Catal. 2020;10:12544-12554. doi: 10.1021/acscatal.0c03420. Epub 2020 Sep 28.
We present a detailed theoretical analysis of the reaction mechanism of proteolysis catalyzed by the main protease of SARS-CoV-2. Using multiscale simulation methods, we have characterized the interactions established by a peptidic substrate in the active site, and then we have explored the free energy landscape associated with the acylation and deacylation steps of the proteolysis reaction, characterizing the transition states of the process. Our mechanistic proposals can explain most of the experimental observations made on the highly similar ortholog protease of SARS-CoV. We point to some key interactions that may facilitate the acylation process and thus can be crucial in the design of more specific and efficient inhibitors of the main protease activity. In particular, from our results, the P1' residue can be a key factor to improve the thermodynamics and kinetics of the inhibition process.
我们对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶催化的蛋白水解反应机制进行了详细的理论分析。使用多尺度模拟方法，我们表征了肽底物在活性位点建立的相互作用，然后探索了与蛋白水解反应的酰化和脱酰化步骤相关的自由能景观，表征了该过程的过渡态。我们的机理推测可以解释对SARS高度相似的直系同源蛋白酶所做的大多数实验观察结果。我们指出了一些可能促进酰化过程的关键相互作用，因此这些相互作用在设计更具特异性和高效性的主要蛋白酶活性抑制剂方面可能至关重要。特别是，从我们的结果来看，P1'残基可能是改善抑制过程的热力学和动力学的关键因素。
