Dynamics of heteropentameric nicotinic acetylcholine receptor: implications of the gating mechanism

The dynamics characteristics of the currently available structure of Torpedo nicotinic acetylcholine receptor (nAChR), including the extracellular, transmembrane, and intracellular domains (ICDs), were analyzed using the Gaussian Network Model (GNM) and Anisotropic Network Model (ANM). We found that a symmetric quaternary twist motion, reported previously in the literature in a homopentameric receptor (Cheng et al. J Mol Biol 2006;355:310-324; Taly et al. Biophys J 2005;88:3954-3965), occurred also in the heteropentameric Torpedo nAChR. We believe, however, that the symmetric twist alone is not sufficient to explain a large body of experimental data indicating asymmetry and subunit nonequivalence during gating. Here we report our results supporting the hypothesis that a combination of symmetric and asymmetric motions opens the gate. We show that the asymmetric motion involves tilting of the TM2 helices. Furthermore, our study reveals three additional aspects of channel dynamics: (1) loop A serves as an allosteric mediator between the ligand binding loops and those at the domain interface, particularly the linker between TM2 and TM3; (2) the ICD can modulate the pore dynamics and thus should not be neglected in gating studies; and (3) the F loops, which are peculiarly longer and poorly-conserved in non-alpha-subunits, have important dynamical implications.