Modelling of ligand–receptor interactions: ab-initio and DFT calculations of solvent reaction field effects on methylated ammonium–π and –acetate complexes

Interaction energies of increasingly methylated ammonium ions with aromatics (benzene, phenol, indole) and with acetate were calculated in vacuo and under the influence of polar media in order to model the binding of ammonium group containing ligands to receptors that offer either carboxylic or aromatic amino acid side chains as ligand anchoring alternatives. Semiempirical, ab-initio and DFT methods were applied to in vacuo calculations while the latter was used at the B3LYP6-31G(d) level in connection with the SCRF procedure of Miertu et al. [Chem. Phys. 55 (1981) 117] to simulate the free energies of transfer from the aqueous (=78.3) to the proteinaceous medium (=20). The in vacuo absolute interaction energies decrease with increasing methylation but the opposite becomes true under the influence of SCRF; only in the example of the tetramethylammonium ion the free energy stays negative. Concerning the interaction of the latter with acetate, it is only slightly more favourable than the binding of tetramethylammonium to indole. This result indicates that aromatic side chains are thermodynamically comparable to the carboxylic ones in the recognition process of the respective receptors for acetylcholine type ligands.