Paper Citing NAMD - Abstract
Stober, Spencer T.; Abrams, Cameron F.
Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors
PROTEIN SCIENCE, 21:307-317, MAR 2012
The soluble acetylcholine binding protein (AChBP) is the default structural proxy for pentameric ligand-gated ion channels (LGICs). Unfortunately, it is difficult to recognize conformational signatures of LGIC agonism and antagonism within the large set of AChBP crystal structures in both apo and ligand-bound states, primarily because AChBP conformations in this set are nearly superimposable (root mean square deviation < 1.5 angstrom). We have undertaken a systematic, alignment-free approach to elucidate conformational differences displayed by AChBP that cleanly differentiate apo/antagonist-bound from agonist-bound states. Our approach uses statistical inference based on both crystallographic states and conformations sampled during long molecular dynamics simulations to select important inter-Ca distances and map their collective values onto functional states. We observe that binding of (nAChR) agonists to AChBP elicits clockwise rotation of the inner beta-sheet with respect to the outer beta-sheet, causing tilting of the cys-loop away from the five-fold axis, in a manner quite similar to that speculated for a-subunits of the heteromeric nAChR structure (Unwin, J Mol Biol 2005;346:967), making this motion potentially important in transmission of the gating signal to the transmembrane domain of a LGIC. The method is also successful at discriminating partial from full agonists and supports the hypothesis that a particularly controversial ligand, lobeline, is in fact an LGIC antagonist.
