The binding energies of the quaternary ions (CH3)4N+ and acetylcholine (ACh) to neutral molecules
have been measured by pulsed high-pressure mass spectrometry and calculated ab initio, to model interactions
in the acetylcholine receptor channel. Binding energies to C6H6 and C6H5CH3 are similar to those to H2O
(33−42 kJ/mol (8−10 kcal/mol)), but are weaker than those to polar organic ligands such as CH3CO2CH3
(50−63 kJ/mol (12−15 kcal/mol)) and to amides (up to 84 kJ/mol (20 kcal/mol)). These data suggest that
aromatic residues that line the groove leading to the ACh receptor site may provide stabilization comparable
to water, and therefore allow entry from the aqueous environment, yet do not bind ACh as strongly as polar
protein groups, and therefore allow transit, without trapping, to the receptor site. Four of the five distinct ACh
conformers located computationally are stabilized by internal C−H···O hydrogen bonds involving the quaternary
ammonium group, which is supported by the thermochemistry of the protonated analogue, CH3CO2CH2CH2N(CH3)2H+, and by the measured bonding energy between models of the ACh end groups, (CH3)4N+ and CH3CO2CH3. Each conformer forms a number of stable complexes with water or benzene. Several possible roles
for an ACh conformational change upon entry into the channel are discussed, including partial compensation
for the loss of bulk solvation. An additional role for the aromatic environment is also suggested, namely
lowering the energy barrier to the formation of the active all-trans ACh rotamer required at the receptor site.
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