Molecular mechanistic exploration of conformational shifts induced by class IV anti-RBD antibody IY2A

The SARS-CoV-2 virus mutates rapidly, reducing the effectiveness of antibodies. The novel Class IV antibody IY2A partially unfolds the receptor-binding domain (RBD), allowing tolerance of antigenic variations and effectively neutralizing Omicron variants. In this study, we used molecular dynamics simulations and alanine scanning combined with interaction entropy method to elucidate how IY2A maintains its binding affinity across Omicron variants. We compared IY2A with EY6A and evaluated how mutations affect IY2A inhibition. The findings revealed that the IY2A adopted a closer conformation when binding to Omicron variants than to the WT. Energy calculations indicate that van der Waals interactions primarily drive IY2A binding to the RBD. Following unfolding, IY2A interacts with the RBD via interatomic hydrogen bonds and hydrophobic contacts involving LEU368, PHE377, LYS378, and SER383. This study provides theoretical insights to guide the development of Class IV antibodies against emerging and future Omicron variants.