Ab initio investigation of interactions between models of membrane-active compounds and polar groups of membranes: complexes involving amine, ether, amide, phosphate, and carboxylate.

Ab initio (MINI-1) molecular orbital calculations were performed on model systems to investigate the hydrogen bonds and proton transfer between antiarrhythmics and polar groups of the cell membrane. Methylamine cation, dimethyl ether, and N-methylacetamide served as models of associative sites for the antiarrhythmics mexiletine and tocainide. Formate and phosphate anions, the methylamine cation, and formamide were chosen as models for the membrane polar groups. Protonated methylamine forms a very strong complex with the formate and phosphate anions. However, the formate COO- group is a better proton acceptor than the phosphate PO4- group. The effect of specific hydration on the proton potential functions was investigated in the HCOO- ... +HNH2CH3 and H2PO4- ... +HNH2CH3 systems. The proton potential functions, calculated at the equilibrium distances RO ... N, with a single minimum were found. The ab initio calculations at the longer RO ... N = 0.275 nm distance indicate double-minimum potentials. The increasing hydration stabilizes a second minimum corresponding to the charged O- ... +HN structures. The complexes involving the amide and ether groups of tocainide and mexiletine and the protonated primary amine group of the membrane are considerably weaker. The weakest hydrogen bonds are formed by the amine group of the drug (in its neutral and ionized state) with the peptide group.