Motivation: The SARS-CoV-2 variants emerging from South Africa (501.V2) and the UK (B.1.1.7) necessitate rapid assessment of the effects of the corresponding amino acid substitutions in the spike (S) receptor-binding domain (RBD) of the variants on the interactions with the human ACE2 receptor and monoclonal antibodies (mAbs) reported earlier to neutralize the spike. Results: Molecular modeling and simulations reveal that N501Y, shared by both variants, increases ACE2 binding affinity, and may impact the collective dynamics of the ACE2-RBD complex, occupying a central hinge site that modulates the overall dynamics of the complex. In contrast, the substitutions K417N and E484K in the South African variant 501.V2 would reduce the ACE2-binding affinity by abolishing two interfacial salt bridges that facilitate RBD binding to ACE2, K417(S)-D30(ACE2) and E484 (S)-K31(ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wildtype RBD. Further analysis of the impact of these mutations on the interactions with mAbs targeting the spike indicate that the substitutions K417N and E484K may also abolish the salt bridges between the spike and selected mAbs, such as REGN10933, BD23, H11_H4, and C105, thus reducing the binding affinity and effectiveness of these mAbs.

中文翻译：

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南非501.V2变体对SARS-CoV-2穗状病毒感染和中和的影响：基于结构的计算评估

动机：来自南非（501.V2）和英国（B.1.1.7）的SARS-CoV-2变体需要快速评估刺突（S）受体结合域中相应氨基酸替代的作用。 （RBD）与人类ACE2受体和单克隆抗体（mAbs）相互作用的变体，已在较早前报道过，以中和该尖峰。结果：分子建模和模拟显示，两个变体共享的N501Y增加了ACE2结合亲和力，并可能影响ACE2-RBD复合物的集体动力学，占据了调节复合物整体动力学的中央铰链位点。相比之下，南非变种501.V2中的取代K417N和E484K将通过取消两个有助于RBD与ACE2结合的界面盐桥来降低ACE2结合亲和力，K417（S）-D30（ACE2）和E484（S）-K31（ACE2）。因此，这两个突变可能不仅仅补偿了由N501Y诱导的吸引作用，总体上导致了与野生型RBD相当的ACE2结合亲和力。进一步分析这些突变对与靶向刺突的mAb相互作用的影响表明，取代K417N和E484K可能也消除了刺突与所选mAb（例如REGN10933，BD23，H11_H4和C105）之间的盐桥，从而降低了这些mAb的结合亲和力和有效性。