Binding of M2 channel inhibitors with enhanced sampling methods
Date:
XXX Annual Meeting of the Reference Network of R+D+I on theoretical and Computational Chemistry
Abstract:
The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. We aim to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine to the wild type M2 channel and its V27A variant using multiple independent molecular dynamics simulations and multiple-walkers well-tempered metadynamics calculations. We propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore.