K+/Na+ selectivity in K channels and valinomycin: over-coordination versus cavity-size constraints

Potassium channels and valinomycin molecules share the exquisite ability to select K(+) over Na(+). Highly selective K channels maintain a special local environment around their binding sites devoid of competing hydrogen bond donor groups, which enables spontaneous transfer of K(+) from states of low coordinations in water into states of over-coordination by eight carbonyl ligands. In such a phase-activated state, electrostatic interactions from these 8-fold binding sites, constrained to maintain high coordinations, result in K(+)/Na(+) selectivity with no need for a specific cavity size. Under such conditions, however, direct coordination from five or six carbonyl ligands does not result in selectivity. Yet, valinomycin molecules achieve selectivity by providing only six carbonyl ligands. Does valinomycin use additional coordinating ligands from the solvent or does it have special structural features not present in K channels? Quantum chemical investigations undertaken here demonstrate that valinomycin selectivity is due to cavity size constraints that physically prevent it from collapsing onto the smaller sodium ion. Valinomycin enforces these constraints by using a combination of intramolecular hydrogen bonds and other structural features, including its specific ring size and the spacing between its connected ligands. Results of these investigations provide a consistent explanation for the experimental data available for the ion-complexation properties of valinomycin in solvents of varying polarity. Together, investigations of these two systems reveal how nature, despite being popular for its parsimony in recycling functional motifs, can use different combinations of phase, coordination number, cavity size, and rigidity (constraints) to achieve K(+)/Na(+) selectivity.