Competition between counterions and active protein sites to bind bisquaternary ammonium groups. A combined mass spectrometry and quantum chemistry model study

A model study of the interaction between biologically active bisquaternary ammonium salts and their molecular targets in living systems is urgently needed to elucidate the molecular mechanisms involved in the interactions between these compounds. To address this need a combined experimental-computational study of the interaction of two tetramethylammonium cations (modeling two quaternary groups) with the chlorine anion and with the deprotonated 2,5-dihydroxybenzoic acid (modeling a carboxylic group and an aromatic ring of side radicals of proteins) has been performed. Fast atom bombardment mass spectrometry method and DFT/B3LYP/6-31++G ** and MP2/6-31++G ** calculations have been employed in the study. Stable noncovalent complexes with different ratios of the tetramethylammonium cations and chlorine anions or deprotonated 2,5-dihydroxybenzoic acid anions were registered in the mass spectra of tetramethylammonium chloride and 2,5-dihydroxybenzoic acid mixture. This finding shows that the organic and inorganic anions compete to bind tetramethylammonium in the studied system. The theoretically determined stabilities of the noncovalent complexes were compared with the relative stabilities evaluated from the mass spectrometric measurements. The results of the study allow us to elucidate the competing interactions that exist between quaternary groups with inorganic counterions or with active groups of molecular protein targets.