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The conformational and property space of acetylcholine bound to muscarinic receptors: an entropy component accounts for the subtype selectivity of acetylcholine.

Abstract：

: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(1) receptor, equally distributed among trans and gauche conformers in M(2), and exclusively gauche in the M(5); the greater flexibility of M(2)-bound ACh was paralleled by the greater flexibility of the occupied M(2) 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 M(2) compared to the M(1) and M(5) 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 M(2)-bound ACh compared to M(1)-bound and M(5)-bound ACh. This finding suggests that the selectivity profile of acetylcholine for the M(2) receptor is largely entropy-driven, a fact that might explain the intrinsic difficulty to design subtype-selective muscarinic agonists.

journal_name

Arch Biochem Biophys

journal_title

Archives of biochemistry and biophysics

authors

Vistoli G,Pedretti A,Testa B,Matucci R

doi

10.1016/j.abb.2007.04.022

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

112-21

issue

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(07)00207-X

journal_volume

464

pub_type

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The conformational and property space of acetylcholine bound to muscarinic receptors: an entropy component accounts for the subtype selectivity of acetylcholine.