Ionic Hydrogen Bonds in Bioenergetics. 4. Interaction Energies of Acetylcholine with Aromatic and Polar Molecules

The binding energies of the quaternary ions (CH 3 ) 4 N + 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 C 6 H 6 and C 6 H 5 CH 3 are similar to those to H 2 O (33−42 kJ/mol (8−10 kcal/mol)), but are weaker than those to polar organic ligands such as CH 3 CO 2 CH 3 (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, CH 3 CO 2 CH 2 CH 2 N(CH 3 ) 2 H +, and by the measured bonding energy between models of the ACh end groups, (CH 3 ) 4 N + and CH 3 CO 2 CH 3 . 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.