A Computational Study of the Closed and Open States of the Influenza A M2 Proton Channel

¹ University of Utah

^* To whom correspondence should be addressed. E-mail: voth{at}chem.utah.edu.

Submitted on May 14, 2005
Revised on June 20, 2005
Accepted on 1 July 2005

	Abstract

In this study, four possible conformations of the His37 and Trp41 residues for the closed state of the influenza M2 ion channel were identified by a conformation scan based on a solid state NMR restraint. In the four conformations, the His37 residue can be of either the t-160 or t60 rotamer, while Trp41 of either the t-105 or t90 rotamer. These conformations were further analyzed by density functional theory calculations and molecular dynamics simulations, and the data indicates that the His37 residue most likely adopts the t60 rotamer and should be mono-protonated at the delta-nitrogen site, while Trp41 adopts the t90 rotamer. This result is consistent with published experimental data and points to a simple gating mechanism: In the closed state, the His37 and Trp41 residues adopt the (t60, t90) conformation, which nearly occludes the pore, preventing non-proton ions from passing through due to the steric and desolvation effects. Moreover, the His37 tetrad interrupts the otherwise continuous hydrogen-bonding network of the pore water by forcing the water molecules above and below it to adopt opposite orientations, thus adding to the blockage of proton shuttling. The channel can be easily opened by rotating the His37 X2 angle from 60 deg to 0 deg. This open structure allows pore water to penetrate the constrictive region and to form a continuous water wire for protons to shuttle through, while being still narrow enough to exclude other ions.

Key Words: M2 channel, gating mechanism, molecular dynamics simulation, proton transport

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