Activation of the Influenza B M2 Proton Channel (BM2)

Influenza B viruses\nhave cocirculated during most seasonal flu\nepidemics and can cause significant human morbidity and mortality\ndue to their rapid mutation, emerging drug resistance, and severe\nimpact on vulnerable populations. The influenza B M2 proton channel\n(BM2) plays an essential role in viral replication, but the mechanisms\nbehind its symmetric proton conductance and the involvement of a second\nhistidine (His27) cluster remain unclear. Here we performed membrane-enabled\ncontinuous constant-pH molecular dynamics simulations on wildtype\nBM2 and a key H27A mutant channel to explore its pH-dependent conformational\nswitch. Simulations captured the activation as the first histidine\n(His19) protonates and revealed the transition at lower pH values\ncompared to AM2 is a result of electrostatic repulsions between His19\nand preprotonated His27. Crucially, we provided an atomic-level understanding\nof the symmetric proton conduction by identifying preactivating channel\nhydration in the C-terminal portion. This research advances our understanding\nof the function of BM2 function and lays the groundwork for further\nchemically reactive modeling of the explicit proton transport process\nas well as possible antiflu drug design efforts.