Gating of acetylcholine receptor channels: brownian motion across a broad transition state.
Acetylcholine receptor channels (AChRs) are proteins that switch between stable "closed" and "open" conformations. In patch clamp recordings, diliganded AChR gating appears to be a simple, two-state reaction. However, mutagenesis studies indicate that during gating dozens of residues across the protein move asynchronously and are organized into rigid body gating domains ("blocks"). Moreover, there is an upper limit to the apparent channel opening rate constant. These observations suggest that the gating reaction has a broad, corrugated transition state region, with the maximum opening rate reflecting, in part, the mean first-passage time across this ensemble. Simulations reveal that a flat, isotropic energy profile for the transition state can account for many of the essential features of AChR gating. With this mechanism, concerted, local structural transitions that occur on the broad transition state ensemble give rise to fractional measures of reaction progress (Phi values) determined by rate-equilibrium free energy relationship analysis. The results suggest that the coarse-grained AChR gating conformational change propagates through the protein with dynamics that are governed by the Brownian motion of individual gating blocks.
Auerbach
Anthony
A
Center for Single Molecule Biophysics and the Department of Physiology and Biophysics, State University of New York, 324 Cary Hall, Buffalo, NY 14214, USA. auerbach@buffalo.edu
D018679:Cholinergic Agonists / Q000494:pharmacology; D003198:Computer Simulation; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008954:Models, Biological; D008962:Models, Theoretical; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*
D018679:Cholinergic Agonists; D007473:Ion Channels; D011950:Receptors, Cholinergic