Biophys J, January 2000, p. 150-163, Vol. 78, No. 1

Computer Simulation of Ion Channel Gating: The M₂ Channel of Influenza A Virus in a Lipid Bilayer

Karl J. Schweighofer^* and Andrew Pohorille^*

 ^*Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, and  Exobiology Branch, NASA Ames Research Center, Moffett Field, California 94035 USA

The transmembrane fragment of the influenza virus M₂ protein forms a homotetrameric channel that transports protons. In this paper, we use molecular dynamics simulations to help elucidate the mechanism of channel gating by four histidines that occlude the channel lumen in the closed state. We test two competing hypotheses. In the "shuttle" mechanism, the  nitrogen atom on the extracellular side of one histidine is protonated by the incoming proton, and, subsequently, the proton on the  nitrogen atom is released on the opposite side. In the "water-wire" mechanism, the gate opens because of electrostatic repulsion between four simultaneously biprotonated histidines. This allows for proton transport along the water wire that penetrates the gate. For each system, composed of the channel embedded in a hydrated phospholipid bilayer, a 1.3-ns trajectory was obtained. It is found that the states involved in the shuttle mechanism, which contain either single-protonated histidines or a mixture of single-protonated histidines plus one biprotonated residue, are stable during the simulations. Furthermore, the orientations and dynamics of water molecules near the gate are conducive to proton transfer. In contrast, the fully biprotonated state is not stable. Additional simulations show that if only two histidines are biprotonated, the channel deforms but the gate remains closed. These results support the shuttle mechanism but not the gate-opening mechanism of proton gating in M₂.

Biophys J, January 2000, p. 150-163, Vol. 78, No. 1
© 2000 by the Biophysical Society   0006-3495/00/01/150/14  $2.00

This article has been cited by other articles:

				Y. Wu and G. A. Voth A Computational Study of the Closed and Open States of the Influenza A M2 Proton Channel Biophys. J., October 1, 2005; 89(4): 2402 - 2411. [Abstract] [Full Text] [PDF]

				V. Vijayvergiya, R. Wilson, A. Chorak, P. F. Gao, T. A. Cross, and D. D. Busath Proton Conductance of Influenza Virus M2 Protein in Planar Lipid Bilayers Biophys. J., September 1, 2004; 87(3): 1697 - 1704. [Abstract] [Full Text] [PDF]

				A. M. Smondyrev and G. A. Voth Molecular Dynamics Simulation of Proton Transport through the Influenza A Virus M2 Channel Biophys. J., October 1, 2002; 83(4): 1987 - 1996. [Abstract] [Full Text] [PDF]

				S. Kim and T. A. Cross Uniformity, Ideality, and Hydrogen Bonds in Transmembrane alpha -Helices Biophys. J., October 1, 2002; 83(4): 2084 - 2095. [Abstract] [Full Text] [PDF]

				J. Wang, S. Kim, F. Kovacs, and T. A. Cross Structure of the transmembrane region of the M2 protein H+ channel Protein Sci., November 1, 2001; 10(11): 2241 - 2250. [Abstract] [Full Text] [PDF]