Ionic hydrogen bonds in bioenergetics. 4. Interaction energies of acetylcholine with aromatic and polar molecules

The binding energies of the quaternary ions(CH3)(4)N+ and acetylcholine (AC h) to neutral molecules have been measured by pulsed high-pressure mass spe ctrometry and calculated ab initio, to model interactions in the acetylchol ine receptor channel, Binding energies to C6H6 and C6H5CH3 are similar to t hose to H2O (33-42 kJ/mol (8-10 kcal/mol)), but are weaker than those to po lar organic ligands such as CH3CO2CH3 (50-63 kJ/mol (12-15 kcal/mol)) and t o 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 aqueo us environment, yet do not bind ACh as strongly as polar protein groups, an d 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, CH3CO 2CH2CH2N(CH3)(2)H+, and by the measured bonding energy between models of th e ACh end groups, (CH3)(4)N+ and CH3CO2CH3. Each conformer forms a number o f 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 fo r the aromatic environment is also suggested, namely lowering the energy ba rrier to the formation of the active all-trans ACh rotamer required at the receptor site.