A theoretical study of the binding of phenothiazine derivatives to residues 82-93 of calmodulin.

A theoretical study was performed of the interaction of four phenothiazine derivatives, promethazine, promazine, trifluopromazine, and trifluoperazine, with a fragment (82-93) of calmodulin, held in the alpha-helical conformation. The computations were performed in the framework of the SIBFA 2 procedure (sum of interactions between fragments computed ab initio), which uses analytical formulas based on ab initio self-consistent field computations. The interaction energy is the sum of the intermolecular phenothiazine-oligopeptide interaction energy and of the separate intramolecular energy variations of the phenothiazine and of the side chains of the oligopeptide upon complex formation. The ordering of interaction energies of the four investigated phenothiazines parallels the ordering of their experimentally measured affinities for calmodulin, with a maximum affinity for trifluoperazine. The principal features of the trifluoperazine complex are a short hydrogen bond between the piperazinium proton and one anionic oxygen of Glu 87, and hydrophobic interactions between the piperazinium ring and Val 91 and between the methylene chain and Ala 88, together with partial insertion of the phenothiazine ring and the--CF3 substituent between Phe 89 and Phe 92.