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

Jianwen Zhang, Yalong Cong, Lili Duan, John Z.H. Zhang

Research output: Contribution to journalArticlepeer-review


The Omicron lineage of SARS-CoV-2, which was first reported in November 2021, has spread globally and become dominant, splitting into several sublineages. Experiments have shown that Omicron lineage has 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 to reveal the escape mechanism of BA.1.1 to monoclonal antibody (mAb) Tixagevimab (AZD1061) and BA.5 to mAb Cilgavimab (AZD8895), both mAbs were combined to form antibody cocktail, Evusheld (AZD7442). The binding free energy of BA.1.1-AZD1061 and BA.5-AZD8895 has been severely reduced due to multiple-site mutated Omicron variants. Our results show that the two Omicron variants, which introduce a substantial number of positively charged residues, can weaken the electrostatic attraction between the receptor binding domain (RBD) and AZD7442, thus leading to a decrease in affinity. Additionally, using umbrella sampling along dissociation pathway, we found that the two Omicron variants severely impaired the interaction between the RBD of SARS-CoV-2’s spike glycoprotein (S protein) and complementary determining regions (CDRs) of mAbs, especially in CDR3H. Although mAbs AZD8895 and AZD1061 are knocked out by BA.5 and BA.1.1, respectively, our results confirm that the antibody cocktail AZD7442 retains activity against BA.1.1 and BA.5 because another antibody is still on guard. The study provides theoretical insights for mAbs interacting with BA.1.1 and BA.5 from both energetic and dynamic perspectives, and we hope this will help in developing new monoclonals and combinations to protect those unable to mount adequate vaccine responses.

Original languageEnglish (US)
Pages (from-to)5297-5308
Number of pages12
JournalJournal of Chemical Information and Modeling
Issue number16
StatePublished - Aug 28 2023

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering
  • Computer Science Applications
  • Library and Information Sciences


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