PT - JOURNAL ARTICLE AU - Feng, Leilei AU - Sun, Zhaoxi AU - Zhang, Yuchen AU - Jian, Fanchong AU - Yang, Sijie AU - Yu, Lingling AU - Wang, Jing AU - Shao, Fei AU - Wang, Xiangxi AU - Cao, Yunlong TI - Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2 AID - 10.1101/2024.09.03.610799 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.09.03.610799 4099 - http://biorxiv.org/content/early/2024/09/04/2024.09.03.610799.short 4100 - http://biorxiv.org/content/early/2024/09/04/2024.09.03.610799.full AB - The recent emergence of SARS-CoV-2 variants KP.2 and KP.3 has been marked by mutations F456L/R346T and F456L/Q493E, respectively, which significantly impact the virus’s interaction with human ACE2 and its resistance to neutralizing antibodies. KP.3, featuring F456L and Q493E, exhibits a markedly enhanced ACE2 binding affinity compared to KP.2 and the JN.1 variant due to synergistic effects between these mutations. This study elucidated the structures of KP.2 and KP.3 RBD in complex with ACE2 using cryogenic electron microscopy (Cryo-EM) and decipher the structural and thermodynamic implications of these mutations on receptor binding by molecular dynamics (MD) simulations, revealing that F456L mutation facilitates a more favorable binding environment for Q493E, leading to stronger receptor interactions which consequently enhance the potential for incorporating additional evasive mutations. These results underscore the importance of understanding mutational epistatic interactions in predicting SARS-CoV-2 evolution and optimizing vaccine updates. Continued monitoring of such epistatic effects is crucial for anticipating new dominant strains and preparing appropriate public health responses.Competing Interest StatementY.C. is a co-founder of Singlomics Biopharmaceutials. Other authors declare no competing interests.