Activation of the influenza B M2 proton channel (BM2)

Abstract Influenza B viruses have co-circulated during most seasonal flu epidemics and can cause significant human morbidity and mortality due to their rapid mutation, emerging drug resistance, and severe impact on vulnerable populations. The influenza B M2 proton channel (BM2) plays an essential role in viral replication, but the mechanisms behind its symmetric proton conductance and the involvement of a second histidine (His27) cluster remain unclear. Here we perform the membrane-enabled continuous constant-pH molecular dynamics simulations on wildtype BM2 and a key H27A mutant to explore its pH-dependent conformational switch. Simulations capture the activation as the first histidine (His19) protonates and reveal the transition at lower pH values compared to AM2 is a result of electrostatic repulsions between His19 and pre-protonated His27. Crucially, we provide an atomic-level understanding of the symmetric proton conduction by identifying pre-activating channel hydration in the C-terminal portion. This research advances our understanding of the function of BM2 function and lays the groundwork for further chemically reactive modeling of the explicit proton transport process as well as possible anti-flu drug design efforts. Competing Interest Statement The authors have declared no competing interest. Abbreviations–The abbreviations used are - BM2 - influenza B M2 proton channel - AM2 - influenza A M2 proton channel - NT - N-terminal - CT - C-terminal - FPS - fixed-protonation-state molecular dynamics - CpHMD - continuous constant-pH molecular dynamics - PT - proton transport - MS-RMD - multiscale reactive molecular dynamics - QM/MM - quantum mechanics/molecular mechanics - HBond - hydrogen-bond - GB - generalized-Born - WT - wildtype - ssNMR - solid-state NMR - POPC - 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine - VM+ - virus-mimetic - RMSD - root-mean-squared deviation - POPE - 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine