RT Journal Article SR Electronic T1 Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.09.03.610799 DO 10.1101/2024.09.03.610799 A1 Feng, Leilei A1 Sun, Zhaoxi A1 Zhang, Yuchen A1 Jian, Fanchong A1 Yang, Sijie A1 Yu, Lingling A1 Wang, Jing A1 Shao, Fei A1 Wang, Xiangxi A1 Cao, Yunlong YR 2024 UL http://biorxiv.org/content/early/2024/09/04/2024.09.03.610799.abstract 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.