Identification of destabilizing SNPs in SARS-CoV2-ACE2 protein and spike glycoprotein: implications for virus entry mechanisms

COVID-19 an outbreak of a novel corona virus originating from Wuhan, China in December 2019 has now spread across the entire world and has been declared a pandemic by WHO. Angiotensin converting enzyme 2 (ACE2) is a receptor protein that interacts with the spike glycoprotein of the host to facilitate the entry of coronavirus (SARS-CoV-2) hence causing the disease (COVID-19). Our experimental design is based on bioinformatics approach that combines sequence, structure and consensus based tools to label a protein coding single nucleotide polymorphism (SNP) as damaging/deleterious or neutral. The interaction of wildtype ACE2-spike glycoprotein and their variants were analyzed using docking studies. The mutations W461R, G405E and F588S in ACE2 receptor protein and population specific mutations P391S, C12S and G1223A in the spike glycoprotein were predicted as highly destabilizing to the structure of the bound complex. So far, no extensive in silico study has been reported that identifies the effect of SNPs on Spike glycoprotein-ACE2 interaction exploring both sequence and structural features. To this end, this study conducted an in-depth analysis that facilitates in identifying the mutations that blocks the interaction of two proteins that can result in stopping the virus from entering the host cell. Communicated by Ramaswamy H. Sarma

2019年12月源自中国武汉的新型冠状病毒（coronavirus）引发的COVID-19疫情，目前已在全球范围内蔓延，且被世界卫生组织（World Health Organization, WHO）列为大流行病。血管紧张素转换酶2（Angiotensin converting enzyme 2, ACE2）是一种受体蛋白，可与宿主的刺突糖蛋白（spike glycoprotein）结合，介导新型冠状病毒（SARS-CoV-2）侵入宿主细胞，进而引发COVID-19疾病。本研究的实验设计基于生物信息学方法，整合序列分析、结构预测与基于共识的工具，将蛋白质编码区的单核苷酸多态性（single nucleotide polymorphism, SNP）划分为有害/损伤性或中性两类。通过分子对接实验，对野生型ACE2-刺突糖蛋白复合物及其变体的相互作用进行了分析。研究预测，ACE2受体蛋白中的W461R、G405E与F588S突变，以及刺突糖蛋白中群体特异性突变P391S、C12S和G1223A，会显著破坏结合复合物的结构稳定性。截至目前，尚未有结合序列与结构特征、系统探究单核苷酸多态性对刺突糖蛋白-ACE2相互作用影响的大规模计算机模拟（in silico）研究被报道。为此，本研究开展了深入分析，旨在筛选出能够阻断两种蛋白相互作用、进而阻止病毒侵入宿主细胞的突变位点。本文由Ramaswamy H. Sarma转交。