Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy.
Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, 45137-66731, Iran.
J Proteome Res. 2020 Nov 6;19(11):4576-4586. doi: 10.1021/acs.jproteome.0c00273. Epub 2020 Jul 1.
SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein.
SARS-CoV-2 引发了 21 世纪最大的一次大流行（COVID-19），威胁到世界各国的生命和经济。寻找能够减轻或控制这一全球健康威胁的新型疗法和疫苗，是生物医学科学面临的最重要挑战之一。为了制定长期战略来对抗 SARS-CoV-2 以及冠状病毒可能带来的其他未来威胁，了解病毒作用的分子机制至关重要。病毒的进入和相关感染性源于 SARS-CoV-2 刺突蛋白与血管紧张素转换酶 2（ACE2）形成复合物。检测病毒刺突蛋白分子上假定的变构位点，可以用来阐明可以用变构药物靶向的分子途径，从而削弱刺突-ACE2 相互作用，降低病毒感染力。在这项研究中，我们介绍了应用不同计算方法来检测 SARS-CoV-2 刺突蛋白变构位点的结果。采用的工具包括蛋白质接触网络（PCN）、SEPAS（通过柔韧性的亲和力）和基于弹性网络模式的扰动响应扫描（PRS）。所有这些方法都应用于 ACE2 与 SARS-CoV2 和 SARS-CoV 刺突蛋白的复合物。所有采用的分析都集中在一个特定的区域（变构调节区 [AMR]），该区域存在于两个复合物中，被预测为调节刺突蛋白与 ACE2 结合的变构位点。对铁调素（一种与 AMR 具有强结构和序列相似性的分子）的初步研究结果表明，它对刺突蛋白与 ACE2 蛋白结合的亲和力具有抑制作用。
