Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell Rep Med. 2022 Jan 24;3(2):100527. doi: 10.1016/j.xcrm.2022.100527. eCollection 2022 Feb 15.
The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBD-RBD interface.
奥密克戎变异株具有增强的传染性和抗体逃逸能力。在这里，我们使用氨基酸相互作用 (AAI) 网络描述奥密克戎受体结合域 (RBD) 的突变景观，这非常适合研究以上位性方式发挥作用的突变组合。通过 AAI，我们直接和间接地映射奥密克戎突变，这些突变驱动了 1-4 类抗体表位的逃逸广度和深度增加。此外，我们还展示了已授权治疗性抗体的表位网络，并评估了每个抗体表位的干扰情况。自奥密克戎出现以来，我们首次建模，这些预测已被 ADG20、AZD8895 和 AZD1061 等治疗性抗体对奥密克戎中和逃逸的实验结果所证实。重要的是，先前的序列或点突变分析并未捕捉到 AAI 预测的间接表位干扰引起的逃逸。最后，对于奥密克戎 RBD 的几个突变，我们发现它们在破坏 RBD-RBD 界面上 RBD 向下构象稳定性方面，可能在增强传染性方面发挥作用。
