Abstract：
As SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to inflict chaos globally, a new variant officially known as B.1.1.529 was reported in South Africa and was found to harbor 30 mutations in the spike protein. It is too early to speculate on transmission and hospitalizations. Hence, more analyses are required, particularly to connect the genomic patterns to the phenotypic attributes to reveal the binding differences and antibody response for this variant, which can then be used for therapeutic interventions. Given the urgency of the required analysis and data on the B.1.1.529 variant, we have performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein. The differences in the binding pattern between the wild type and B.1.1.529 variant complexes revealed that the key substitutions Asn417, Ser446, Arg493, and Arg498 in the B.1.1.529 RBD caused additional interactions with hACE2 and the loss of key residues in the B.1.1.529 NTD resulted in decreased interactions with three CDR regions (1-3) in the mAb. Further investigation revealed that B.1.1.529 displayed a stable dynamic that follows a global stability trend. In addition, the dissociation constant (KD), hydrogen bonding analysis, and binding free energy calculations further validated the findings. Hydrogen bonding analysis demonstrated that significant hydrogen bonding reprogramming took place, which revealed key differences in the binding. The total binding free energy using MM/GBSA and MM/PBSA further validated the docking results and demonstrated significant variations in the binding. This study is the first to provide a basis for the higher infectivity of the new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them.
摘要：
随着SARS-CoV-2（严重急性呼吸道综合症冠状病毒2）继续在全球造成混乱，在南非报道了一种正式称为B.1.1.29的新变体，该变体在刺突蛋白中发现了30个突变。现在推测传播和住院还为时过早。因此，需要更多的分析，特别是将基因组模式与表型属性联系起来，以揭示该变体的结合差异和抗体反应，然后可以用于治疗干预。鉴于B.1.1.529变体所需的分析和数据的紧迫性，我们进行了详细的调查，以了解这些新突变对结构的影响，函数,RBD与hACE2的结合和mAb与刺突蛋白的NTD的结合。野生型和B.1.1.529变体复合物之间结合模式的差异表明，B.1.1.529RBD中的关键取代Asn417，Ser446，Arg493和Arg498引起与hACE2的额外相互作用，并且B.1.1.529NTD中关键残基的丢失导致与mAb中三个CDR区（1-3）的相互作用减少。进一步的调查显示，B.1.1.529显示出遵循全球稳定趋势的稳定动态。此外,解离常数(KD)，氢键分析,结合自由能计算进一步验证了研究结果。氢键分析显示发生了显著的氢键重编程,这揭示了绑定中的关键差异。使用MM/GBSA和MM/PBSA的总结合自由能进一步验证了对接结果并证明了结合的显著变化。本研究首次为SARS-CoV-2新变种的较高传染性提供了依据，并为开发针对其的新药提供了强大的动力。
