Singh Jasdeep, Vashishtha Shubham, Rahman Syed Asad, Ehtesham Nasreen Zafar, Alam Anwar, Kundu Bishwajit, Dobrindt Ulrich
Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India.
Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India.
Biochemistry. 2022 Oct 18;61(20):2188-2197. doi: 10.1021/acs.biochem.2c00301. Epub 2022 Sep 27.
The receptor binding domain(s) (RBD) of spike (S) proteins of SARS-CoV-1 and SARS-CoV-2 (severe acute respiratory syndrome coronavirus) undergoes closed to open transition to engage with host ACE2 receptors. In this study, using multi atomistic (equilibrium) and targeted (non-equilibrium) molecular dynamics simulations, we have compared energetics of RBD opening pathways in full-length (modeled from cryo-EM structures) S proteins of SARS-CoV-1 and SARS-CoV-2. Our data indicate that amino acid variations at the RBD interaction interface can culminate into distinct free energy landscapes of RBD opening in these S proteins. We further report that mutations in the S protein of SARS-CoV-2 variants of concern can reduce the protein-protein interaction affinity of RBD(s) with its neighboring domains and could favor its opening to access ACE2 receptors. The findings can also aid in predicting the impact of future mutations on the rate of S protein opening for rapid host receptor scanning.
严重急性呼吸综合征冠状病毒1型（SARS-CoV-1）和2型（SARS-CoV-2）刺突（S）蛋白的受体结合域（RBD）会经历从关闭到开放的转变，以与宿主血管紧张素转换酶2（ACE2）受体结合。在本研究中，我们使用多原子（平衡）和靶向（非平衡）分子动力学模拟，比较了SARS-CoV-1和SARS-CoV-2全长S蛋白（根据冷冻电镜结构建模）中RBD开放途径的能量学。我们的数据表明，RBD相互作用界面处的氨基酸变异可导致这些S蛋白中RBD开放的自由能景观截然不同。我们进一步报告称，值得关注的SARS-CoV-2变体的S蛋白中的突变可降低RBD与其相邻结构域的蛋白质-蛋白质相互作用亲和力，并可能有利于其开放以接近ACE2受体。这些发现也有助于预测未来突变对S蛋白快速扫描宿主受体的开放速率的影响。
