Conformational Heterogeneity Of The M2 Proton Channel: A Model For Channel Activation

Abstract

The M2 protein of influenza A is a proton selective ion channel activated by low pH. Recent structures determined by X-ray crystallography and solution NMR suggested models for open and closed states. However, these models are based on limited data and other important functional states need to be characterized. Indeed, solid-state NMR data demonstrate that the M2 protein possesses significant conformational heterogeneity. Here, we report MD simulations of the M2 transmembrane domain in the absence and presence of the anti-viral drug, amantadine. The ensembles of MD conformations for both apo and bound forms reproduce the PISEMA data well (Figure). The helices kink around Gly34, where a water molecule penetrates deeply into the backbone. The bound form exhibits a single peak around 10° in the distribution of helix kinking angle, but the apo form exhibits two peaks, around 0° and 40°. Conformations with the larger kinking angles have a wider opening around the primary gate formed by His37 and Trp41, reproducing some of the key observations on the low-pH activated state by 19F NMR. We propose that this population is stabilized by low pH and leads to proton conductance.View Large Image | View Hi-Res Image | Download PowerPoint Slide