Combined Antibodies Evusheld against the SARS-CoV-2 Omicron Variants BA.1.1 and BA.5: Immune Escape Mechanism from Molecular Simulation

作者：Zhang, Jianwen; Cong, Yalong; Duan, Lili^*; Zhang, John Z. H.

来源：Journal of Chemical Information and Modeling, 2023, 63(16): 5297-5308.

DOI：10.1021/acs.jcim.3c00813

• INTERACTION ENTROPY
• FREE-ENERGY
• BINDING
• EFFICIENT
• DYNAMICS
• SURFACE

The Omicron lineage of SARS-CoV-2, which was first reportedinNovember 2021, has spread globally and become dominant, splittinginto several sublineages. Experiments have shown that Omicron lineagehas escaped or reduced the activity of existing monoclonal antibodies,but the origin of escape mechanism caused by mutation is still unknown.This work uses molecular dynamics and umbrella sampling methods toreveal the escape mechanism of BA.1.1 to monoclonal antibody (mAb)Tixagevimab (AZD1061) and BA.5 to mAb Cilgavimab (AZD8895), both mAbswere combined to form antibody cocktail, Evusheld (AZD7442). The bindingfree energy of BA.1.1-AZD1061 and BA.5-AZD8895 has been severely reduceddue to multiple-site mutated Omicron variants. Our results show thatthe two Omicron variants, which introduce a substantial number ofpositively charged residues, can weaken the electrostatic attractionbetween the receptor binding domain (RBD) and AZD7442, thus leadingto a decrease in affinity. Additionally, using umbrella sampling alongdissociation pathway, we found that the two Omicron variants severelyimpaired the interaction between the RBD of SARS-CoV-2's spikeglycoprotein (S protein) and complementary determining regions (CDRs)of mAbs, especially in CDR3(H). Although mAbs AZD8895 andAZD1061 are knocked out by BA.5 and BA.1.1, respectively, our resultsconfirm that the antibody cocktail AZD7442 retains activity againstBA.1.1 and BA.5 because another antibody is still on guard. The studyprovides theoretical insights for mAbs interacting with BA.1.1 andBA.5 from both energetic and dynamic perspectives, and we hope thiswill help in developing new monoclonals and combinations to protectthose unable to mount adequate vaccine responses.

• 单位
  中国科学院