The COVID-19 pandemic poses significant challenges to global public health, demanding urgent and effective measures to overcome the virus. As of September 12, 2022, over 12 billion vaccine doses have been administered globally. By the end of 2021, eight therapeutic neutralizing antibody (nAb)-based drugs targeting SARS-CoV-2 had received Emergency Use Authorization approval from the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA). However, the virus continues to evolve, giving rise to numerous variants. The World Health Organization (WHO) has designated certain variants with increased virulence, such as Alpha, Beta, Gamma, Delta, and Omicron, as Variants of Concern (VOC). Among these, Omicron has evolved into multiple subvariants: BA.2, BA.3, BA.4, and BA.5. The emergence of viral variants has raised concerns about the effectiveness of currently available coronavirus vaccines. Many studies have reported high immune evasion capabilities of the Omicron variant and its subvariants. Therefore, systematically analyzing the impact of spike protein mutations on antibody binding is crucial to guide the design of broad-spectrum antibodies.

In this study, we first constructed structural models of spike antibody complexes based on experimental structures. Subsequently, we evaluated the system binding free energy (ΔGbinding) and binding free energy changes (ΔΔGbinding) to assess differences in affinity among eight nAbs (AZD1061, AZD8895, CT-P59, LY-COV555, LY-COV016, REGN10933, REGN10987, and S309) towards eight viral variants (Alpha, Beta, Gamma, Delta, Omicron BA.1, Omicron BA.2, Omicron BA.3, and Omicron BA.4; BA.4 and BA.5 share the same mutations). By analyzing ΔΔGbinding values, we designed a scoring method to assess the immune evasion capabilities of viral variants. Additionally, we analyzed the differences in ΔGbinding and ΔΔGbinding during the binding process of the ACE2 receptor with two patient-derived antibodies (P22A and 510A5) and artificially designed antibody mimetics (AHB2). Furthermore, we discussed potential directions for future antibody design. Our results may provide valuable insights for the development of more effective therapeutic approaches to combat SARS-CoV-2 and its variants.