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

Abstract

The PB2 cap binding domain (PB2cap) of influenza virus is considered as the important target to block viral transcription due to the cap-binding. The lack of the complex structures of PB2cap with m7GDP limit to explore the binding differences of influenza A and B viruses (FluA and FluB) PB2cap with methylated cap analogs (m7GTP and m7GDP). In this study, based on the complex structures of FluA-D, FluB-D by Discovery Studio 3.1 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 over m7GDP for FluA and FluB, with pronounced FluA than 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 ana-logs may explain the differences in binding abilities. Besides, the sandwich structure, π-π stacking interaction and electrostatic interaction between PB2cap and methylated cap analogs are the key factors to stabilize positioning in the binding pockets. Our work could provide some valuable theoretical clues for the development of influenza viruses PB2 inhibitors.