Koley Tirthankar, Goswami Arunima, Kumar Manoj, Upadhyay Neelam, Hariprasad Gururao
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, India.
Adv Appl Bioinform Chem. 2022 Jun 16;15:21-27. doi: 10.2147/AABC.S360787. eCollection 2022.
Spike protein on SARS-CoV-2 virus plays an integral part during infection as cell entry depends on binding of this protein to human ACE2 receptor. Understanding of infectivity by these variants necessitates a comparative structural analysis of complexes of spike protein-receptor binding domain (RBD) of these variants to receptor.
Wild type SARS-CoV-2 spike protein sequence was retrieved from the UniProt database, and mutations of five variants at receptor binding domain were manually incorporated and aligned using Clustal Omega. Crystal structure complexes of human ACE2 receptor with spike protein RBD domain of SARS-CoV-2 variants of wild type, α, β, and δ were extracted from the RCSB database. Wild type SARS-CoV-2 complex with receptor was used as template to generate model complexes of receptor with spike protein RBD of γ and omicron variants through WinCoot program. These were energy minimized and validated and molecular dynamic simulation was performed using Desmond simulation program.
Mutations are distributed across the entire length of RBD, but the maximum number of mutations are seen at 11 positions within binding interface motifs of six variant sequences. Interface of spike protein RBDs with human ACE2-receptor shows different mix of hydrogen bonded and ionic interactions. Alpha and β variants have few interactions, while γ and δ variants have higher number of interactions compared to wild type variant. Omicron variant, with 10 polar interactions including two ionic bonds, has the highest binding energy.
Different mutations on RBD of spike protein results in varying quantity and quality of interactions, thereby affecting potency of each variant. Variations in binding are due to interactions of mutant residues and induced conformational changes on loops of RBDs. Variants α and β have a low potency, while, γ, δ, and omicron have a higher potency. These results correlate with viral infectivity and place clinical observations in the right perspective.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒上的刺突蛋白在感染过程中起着不可或缺的作用，因为细胞进入取决于该蛋白与人血管紧张素转换酶2（ACE2）受体的结合。要了解这些变体的传染性，就需要对这些变体的刺突蛋白受体结合域（RBD）与受体的复合物进行比较结构分析。
从UniProt数据库中检索野生型SARS-CoV-2刺突蛋白序列，并手动纳入5个变体在受体结合域的突变，使用Clustal Omega进行比对。从RCSB数据库中提取人ACE2受体与野生型、α、β和δ型SARS-CoV-2变体的刺突蛋白RBD结构域的晶体结构复合物。以野生型SARS-CoV-2与受体的复合物为模板，通过WinCoot程序生成γ和奥密克戎变体的受体与刺突蛋白RBD的模型复合物。对这些复合物进行能量最小化和验证，并使用Desmond模拟程序进行分子动力学模拟。
突变分布在RBD的全长范围内，但在6个变体序列的结合界面基序内的11个位置出现的突变数量最多。刺突蛋白RBD与人ACE2受体的界面显示出氢键和离子相互作用的不同组合。α和β变体的相互作用较少，而γ和δ变体与野生型变体相比有更多的相互作用。奥密克戎变体有10个极性相互作用，包括两个离子键，具有最高的结合能。
刺突蛋白RBD上的不同突变导致相互作用的数量和质量不同，从而影响每个变体的效力。结合的变化是由于突变残基的相互作用以及RBD环上诱导的构象变化。α和β变体的效力较低，而γ、δ和奥密克戎变体的效力较高。这些结果与病毒传染性相关，并正确地呈现了临床观察结果。
