  To what extent must a hydrophobic gate expand for the channel to count as
open? We address this question using the nicotinic acetylcholine receptor
(nAChR) as the exemplar. The nAChR is an integral membrane protein which forms
a cation selective channel gated by neurotransmitter binding to its
extracellular domain. A hydrophobic gating model has been proposed for the
nAChR, whereby the pore is incompletely occluded in the closed state channel,
with a narrow hydrophobic central gate region which presents an energetic
barrier to ion permeation. The nAChR pore is lined by a parallel bundle of five
M2 alpha-helices, with the gate formed by three rings of hydrophobic sidechains
(9', 13', and 17' of M2). A number of models have been proposed to describe the
nature of the conformational change underlying the closed to open transition of
the nAChR. These models involve different degrees of M2 helix displacement,
rotation, and/or kinking. In this study, we use a simple pore expansion method
(previously used to model opening of potassium channels) to generate a series
of progressively wider models of the nAChR transmembrane domain. Continuum
electrostatics calculations are used to assess the change in the barrier height
of the hydrophobic gate as a function of pore expansion. The results suggest
that an increase in radius of Delta r ~ 1.5 angstrom is sufficient to
functionally open the pore without, for example, a requirement for rotation of
the M2 helices. This is evaluated in the context of current mutational and
structural data on the nAChR and its homologues.
