SARS-CoV-2 JN.1 Spike: insights into its structure, function, and implications

Since its first appearance in China, SARS-CoV-2 has undergone relentless molecular evolution, with the spike protein playing a key role in transmission and evasion of host immune surveillance. In this work spike proteins of the JN.1 variant and the earlier BA.2 were compared to identify structural differences related to virus adaptation and evolution. Mutations in N-terminal Domain (NTD) and Receptor Binding Domain (RBD) were assessed using homology modeling and molecular dynamics (MD). Binding energy and surface electrostatic potential were calculated by sampling frames at regular intervals from MD simulations. Moreover, an analysis on the effect of the Val483 deletion, detected near a loop at JN.1 RBD-ACE2 interface with a prevalence of 83.2%, was also conducted. Results show an increased RBD net charge in JN.1 (+7.5 vs. BA.2's +6.2) and a more negative NTD net charge (-1.7 vs. BA.2's +1.2). Molecular dynamics experiments reveal that mutations in JN.1 alter the flexibility of loops in both the RBD and NTD compared to BA.2. Altered trajectories of the RBD-ACE2 interface loop were observed especially in the presence of the Val483 deletion, indicating a potential destabilization of the ACE2 interaction. Thus, this observation might explain the RBD resistance to deletions. Examination of the molecular evolutionary trajectory of SARS-CoV-2 may help unravel principles of interest in protein evolution and monitor the emergence of new potentially dangerous variants, with the aim of informing the development of adaptive strategies to mitigate the impact on global public health.