Association energies of the acetate ion with cationic amines bearing one to three methyl groups were calculated in the range of -14 to -17 kcal/mol in aqueous solution by means of the IEF-PCM method at the CCSD(T)/CBS//MP2/aug-cc-pvdz and DFT/B97D/CBS//B97D/aug-cc-pvtz levels. The main stabilization factor for the association is the possibility for the formation of an ionic intermolecular hydrogen bond between the elements of the complex. For a quaternary ammonium ion, the favorable electrostatic interaction energy is the only driving force, and the stabilization energy for the complex is reduced to -4 kcal/mol. The internal free energies of the ion-pair tautomers of the studied species are higher by 10-15 kcal/mol in water than those for the neutral, hydrogen-bonded forms. Monte Carlo free energy perturbation calculations at T = 298 K and p = 1 atm predict -11 to -16 kcal/mol relative solvation free energy in favor of the corresponding ionic form. As a result, the ion-pair tautomer is the prevailing form in aqueous solution and on the extracellular surface of a receptor. Modeling the complex of a protonated ligand interacting with an Asp/Glu carboxylate side-chain in the binding cavity of a receptor, two strongly bound water molecules were considered so as to form hydrogen-bonded water bridges between the elements of the ion-pair. Nonetheless, the low polarity environment mimicked by a chloroform solvent cannot stabilize the ionic tautomer. A proton jump was predicted, which suggests that acetylcholine, an inherent cation by structure, might have evolved as the natural agonist for muscarinic receptors because a quaternary ammonium system assures the maintenance of the ion-pair form with a carboxylate side-chain in a protein cavity, the latter perhaps then being needed for receptor activation.