Selectivity mechanism of the PB2 cap-binding domain of influenza A and B viruses for methylated cap analogs: insights from MD simulations

The PB2 cap-binding domain (PB2_cap) of the influenza virus is considered an important target for blocking viral transcription due to its cap binding. The lack of the complex structures of PB2_cap with m⁷GDP limits the exploration of the binding differences between the PB2_cap of influenza A and B viruses (FluA and FluB, respectively) with methylated cap analogs (m⁷GTP and m⁷GDP). In this study, based on the complex structures of FluA-D and FluB-D obtained using Discovery Studio 2.5 software and the crystal structures of FluA and FluB with m⁷GTP (FluA-T and FluB-T), we investigated the binding of FluA and FluB with m⁷GTP and m⁷GDP by molecular dynamics simulations and MM-GBSA calculations. The results show that m⁷GTP binding affinity is greater than that of m⁷GDP for FluA and FluB, with a more pronounced affinity for FluA than that for FluB. The differences in the properties of the key residues of FluA (F323, H357 and N429) and FluB (Q325, W359 and S431) and the structures of the methylated cap analogs may explain the differences in binding abilities. Besides, the sandwich structure, π-π stacking interactions, and the electrostatic interactions between PB2_cap and methylated cap analogs are the key factors in stabilizing the positioning in the binding pockets. Our work could provide some valuable theoretical clues for the development of influenza virus PB2 inhibitors.