Paper Citing NAMD - Abstract
Vistoli, Giulio; Pedretti, Alessandro; Testa, Bernard; Matucci, Rosanna
The conformational and property space of acetylcholine bound to muscarinic receptors: An entropy component accounts for the subtype selectivity of acetylcholine
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 464:112-121, AUG 1 2007
The conformational behavior of receptor-bound acetylcholine (ACh) was investigated by molecular dynamics simulations. Based on the great similarity among muscarinic receptors, the study was focused on the human M-1, M-2, and M-5 receptors as previously modeled by us. The results showed that receptor-bound ACh was not frozen in a single preferred conformation but preserved an unexpected fraction of its conformational space. However, there were marked differences between the three receptors since the ligand was mostly trans in the M, receptor, equally distributed among trans and gauche conformers in M2, and exclusively gauche in the M5; the greater flexibility of M-2-bound ACh was paralleled by the greater flexibility of the occupied M2 binding site. By contrast, the property space of receptor-bound ACh, and particularly its virtual (computed, conformation-dependent) lipophilicity, was restricted to relatively narrow ranges optimal for successful interaction. Experimental binding investigations to the individual human M-1, M-2, and M-5 muscarinic receptors showed ACh to have a 10-fold higher affinity for the M2 compared to the M, and M5 receptors. This selectivity was not confirmed by the calculated binding scores, a fact postulated to be caused by the absence of an entropy component in such binding scores. Indeed, the Shannon entropy of all geometric and physicochemical properties monitored were markedly higher in M2-bound ACh compared to M-1-bound and M-5-bound ACh. This finding suggests that the selectivity profile of acetylcholine for the M2 receptor is largely entropy-driven, a fact that might explain the intrinsic difficulty to design subtype-selective muscarinic agonists. (c) 2007 Elsevier Inc. All rights reserved.
