Mechanism of Proton Transport in Influenza A M2 Mutant From Multiscale Simulations

Laura Watkins, University of Chicago

The influenza A virus M2 channel (AM2) is a homotetrameric acid-activated proton channel responsible for the acidification of the virus interior, a crucial step in the viral life cycle. One important feature of this channel is its asymmetric conductance: inward proton flux is allowed when the exterior pH is low and the viral interior pH is high, but reverse proton flux is prohibited under a reversed pH gradient. However, the mechanism of this asymmetry is not fully understood. It has been indicated that four tryptophan residues (Trp41) form a gate that results in asymmetric conduction, and another residue, Asp44, is critical for maintaining the stability of this gate. Here, multiscale computer simulations are used to characterize proton transport through an Asp44 mutant that exhibits both increased conduction and an altered asymmetric conductance. Classical, QM/MM, and reactive molecular dynamics methods are bridged in a multiscale fashion to determine explicit proton transport free energy profiles through the channel and to deduce the mechanism of asymmetric conductance. This work shows how this mutation results in different proton conduction behavior and the role of these critical residues.

Abstract Author(s): Laura Watkins, Ruibin Liang, Jessica M. J. Swanson, Gregory Voth