Conformational dynamics of the carboxylic ionophore lasalocid A underlying cation complexation-decomplexation and...

The conformational dynamics of lasalocid A have been studied in a series of solvents of graded polarity by means of circular dichroism (CD) and computer-generated molecular models. In high polarity solvents, the uncomplexed anionic ionophore assumes as acyclic conformation minimizing intrinsic molecular strain energy. In this state, the dipoles of the liganding oxygens in the carbon backbone and the terminal carboxylate are stabilized by a high degree of solvent association. As the solvent polarity decreases, the dynamic conformational equilibrium progressively shifts toward a cyclic conformation which predominates at low polarity. Cyclization proceeds by rotation about three carbon-carbon hinge bonds. The resulting twist of the backbone introduces torsional strain which is offset at low polarity by electrostatic stabilization gained through intramolecular hydrogen bonding. Formation of a cation inclusion complex also stabilizes the cyclic conformer, even in relatively polar solvents. These observations suggest a scenario for carboxylic ionophore mediated transmembrane monovalent cation transport at the molecular level. The cation encounters an acyclic ionophore at the membrane interface where it ion pairs to the terminal carboxylate moiety, initiating formation of a lipophilic, cyclic cation inclusion complex. The complex, no longer constrained to the polar interface, diffuses across the membrane interior to the opposite face. There it reequilibrates with the polar environment, the ionophore reassuming the low energy, acyclic conformation and concomitantly releasing the enclosed cation. The free, acyclic ionophore is now confined to the opposite polar interface where it awaits the capture of a new cation to complete its catalytic transport cycle.