Model exploring the mechanistic basis for altered SARS-CoV-2 RdRp activity upon encountering methylation of adenosine in the +1 position (+1 A). The +1 A is shown with white sticks, RdRp amino acid residues proximal to the +1 nucleic acid residue are shown as blue sticks and labeled, hydrogen bonding interactions are shown with dashed yellow lines, and relevant distances are shown with a red dashed line. (A, B) The +1 A with no modifications. The +1 A 2′OH forms a hydrogen bond with the backbone of G683 (yellow arrow). (C, D) N6-methylation modestly increases the potential for steric clashes with K545 (red arrow). (E, F) 2′-O-methylation eliminates hydrogen bonding with G683 and introduces clashes (red arrow). Structures are based on PDB 6YYT (Hillen et al. 2020).
