Peculiar variations of the electrostatic potential of spike protein N-terminal domain associated with the emergence of successive SARS-CoV-2 Omicron lineages

Zeng and collaborators (1) have recently discussed the potential of the porcine tyrosine-protein kinase receptor UFO (AXL) to inter- act with the N-terminal domain (NTD) of the spike (S) protein of some SARS-CoV-2 Variants of Concern (VOC). Omicron (BA.1.1.529) is the last VOC that, after its first detection in South Africa in the late 2021, has spread worldwide and has generated several sub- variants of which those belonging to the BA.2 lineage (BA.2.12.1, BA.4 and BA.5) are now the most prevalent in several countries (www.who.int). Omicron subvariants markedly differ in resistance to antibody neutralization, that has been largely attributed to changes in the mutational landscape of RBD region of the Spike (S) protein (2) Little comparative attention is currently reserved to the mutational landscape of the S protein NTD although this domain also carries a distinctive set of mutations which markedly distin- guish BA.1 (and BA.3) from the subvariants of the BA.2 lineage (BA.2.12.1,and BA4/5). In addition, BA.4 and BA.5 carry a HV69-70 deletion that is absent in the BA.2 and BA.2.12.1 subvariants. We have recently shown that the mutational landscape of both RBD and NTD largely determines their net surface charge, i.e. an in- direct estimate of the dominant charge of the surface electrostatic potential (EP) (3,4)