多种严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体继续进化，在刺突蛋白受体结合域（RBD）中携带柔性氨基酸取代。这些取代改变了SARS-CoV-2与人血管紧张素转换酶2（hACE2）受体的结合，并与改变的宿主适应性有关。针对抗体疗法和疫苗的传播性和功效。可靠地预测SARS-CoV-2变体RBD与hACE2受体和中和抗体（NAb）的结合强度可以帮助评估它们的适应性。快速部署有效的抗体疗法，分别。这里,我们引入了一个两步计算框架,并进行了3倍验证,首先确定了解离常数是异源二聚体和三聚体蛋白复合物中结合亲和力的可靠预测指标.第二步实现解离常数作为SARS-CoV-2变体RBD与hACE2和NAb的结合强度的描述符。然后，我们检查了几种关注变量（VOC），如Alpha，Beta,Gamma,Delta,和Omicron，并证明这些VOCsRBD以增强的亲和力与hACE2结合。此外，Omicron变体的RBD的结合亲和力随着大多数RBD定向的NAb而降低，这与实验中和数据高度一致。通过研究RBD和NAb之间的原子接触，我们揭示了4种NAb(GH-12,P2B-1A1,Asarnow_3D11和C118)的分子足迹,这可能会中和最近出现的Omicron变体-促进结合亲和力增强.最后,我们的研究结果提示了一个计算通路,该通路可以帮助研究人员确定一系列可能对新出现的SARS-CoV-2变异有效的当前NAb.本文受版权保护。保留所有权利。
Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to evolve carrying flexible amino acid substitutions in the spike protein\'s receptor binding domain (RBD). These substitutions modify the binding of the SARS-CoV-2 to human angiotensin-converting enzyme 2 (hACE2) receptor and have been implicated in altered host fitness, transmissibility, and efficacy against antibody therapeutics and vaccines. Reliably predicting the binding strength of SARS-CoV-2 variants RBD to hACE2 receptor and neutralizing antibodies (NAbs) can help assessing their fitness, and rapid deployment of effective antibody therapeutics, respectively. Here, we introduced a two-step computational framework with 3-fold validation that first identified dissociation constant as a reliable predictor of binding affinity in hetero- dimeric and trimeric protein complexes. The second step implements dissociation constant as descriptor of the binding strengths of SARS-CoV-2 variants RBD to hACE2 and NAbs. Then, we examined several variants of concerns (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron and demonstrated that these VOCs RBD bind to the hACE2 with enhanced affinity. Furthermore, the binding affinity of Omicron variant\'s RBD was reduced with majority of the RBD-directed NAbs, which is highly consistent with the experimental neutralization data. By studying the atomic contacts between RBD and NAbs, we revealed the molecular footprints of four NAbs (GH-12, P2B-1A1, Asarnow_3D11, and C118)-that may likely neutralize the recently emerged Omicron variant-facilitating enhanced binding affinity. Finally, our findings suggest a computational pathway that could aid researchers identify a range of current NAbs that may be effective against emerging SARS-CoV-2 variants.
