Counterintuitive Electrostatics upon Metal Ion Coordination to a Receptor with Two Homotopic Binding Sites

The consecutive binding of two potassium ions to a bis(18-crown-6) analogue of Troger's base (BCETB) in water was studied by isothermal titration calorimetry using four different salts, KCl, KI, KSCN, and K2SO4. A counterintuitive result was observed: the enthalpy change associated with the binding of the second ion is more negative than that of the first (Delta H-bind,H-2 degrees < Delta H-bind,H-1 degrees). This remarkable finding is supported by continuum electrostatic theory as well as by atomic scale replica exchange molecular dynamics simulations, where the latter robustly reproduces experimental trends for all simulated salts, KCl, KI, and KSCN, using multiple force fields. While an enthalpic K+-K+ attraction in water poses a small, but fundamentally important, contribution to the overall interaction, the probability of the collapsed conformation (COL) of BCETB, where both crown ether moieties (CEs) of BCETB are bent in toward the cavity, was found to increase successively upon binding of the first and second potassium ions. The promotion of the COL conformation reveals favorable intrinsic interactions between the potassium coordinated CEs, which further contribute to the observation that Delta H-bind,H-2 degrees < Delta H-bind,H-1 degrees. While the observed trend is independent of the counterion, the origin of the significantly larger magnitude of the difference Delta H-bind,H-2 degrees - Delta H-bind,H-1 degrees observed experimentally for KSCN was studied in light of the weaker hydration of the thiocyanate anion, resulting in an enrichment of thiocyanate ions close to BCETB compared to the other studied counterions.