SARS-CoV-2 BA.2.86 Spike: insights into its structure, function, and implications

Since its first appearance in China, SARS¬CoV¬2 has undergone significant molecular evolution, with the spike protein playing a key role in transmission and evasion of host immune surveillance. In this work, we analyzed the spike protein of BA.2.86 variant, commonly known as Pirola, and its earlier variants to identify structural differences related to virus adaptation and evolution. We evaluated the effects of mutations in N¬terminal Domain (NTD) and Receptor Binding Domain (RBD) using homology modeling, binding energy prediction, surface electrostatic potential analysis and molecular dynamics. Furthermore, we analyzed in detail the effect of the Val483 deletion, detected in a loop near BA.2.86 RBD interface with ACE2 with a prevalence of about 70%. The results indicated an increase in the net charge of the RBD of BA.2.86 up to +6.6 compared to +5.5 of XBB lineage variants, while the NTD was found to have a more negative net charge (¬1.7) compared to the NTDs of the earlier variants. Binding energy predictions suggest BA.2.86¬ACE2 complexes are slightly more stable than those formed by the earlier variants. According to the results of molecular dynamics experiments, mutations in BA.2.86 alter the flexibility of loops in both RBD and NTD compared to the original wild¬type virus. Furthermore, we observed an alteration in the dynamic trajectory of the interface loop in the presence of Val483 deletion, which may indirectly destabilize the interaction with the receptor ACE2. This observation could explain the RBD resistance to deletions. Examining the molecular evolutionary trajectory of SARS¬CoV¬2 may help unravel principles of broad 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.