Charge transfer across biomembranes: A solution to the conundrum of high desolvation free energy penalty in ion transport.

Charge transfer across membranes is an important problem in a wide variety of fundamental physicochemical and biological processes. Since Mitchell's concept of the ion well advanced in 1968, several models of ion translocation across biomembranes, for instance through the membrane-bound F portion of ATP synthase have been proposed. None of these models has considered the large desolvation free energy penalty of ~500 meV incurred in transferring a protonic charge from the aqueous phase into the membrane that hinders such charge transfer processes. The difficulty has been pointed out repeatedly. However, the problem of how the adverse ∆G barrier is overcome in order to enable rapid ion translocation in biomembranes has not been satisfactorily resolved. Hence the fact that the self-energy of the charges has been overlooked can be regarded as a main source of confusion in the field of bioenergetics. Further, in order to consider charges of a finite size (and not just point charges), the free energy of transferring the ions from water into a membrane phase of lower dielectric ε needs to be evaluated. Here a solution to the longstanding conundrum has been proposed by including the bound anion - the second ion in Nath's two-ion theory of energy coupling and ATP synthesis - in the free energy calculations. The mechanistic importance of the H - A charge pair in causing rotation and ATP synthesis by ion-protein interactions is highlighted. The ∆G calculations have been performed by using the Kirkwood-Tanford-Warshel (KTW) theory that takes into account the self-energies of the ions. The results show that the adverse ∆G can be almost exactly compensated by the sum of the electrostatic free energy of the charge-charge interactions and the dipole solvation energy for long-range ion pairs. Results of free energy compensation using the KTW theory have been compared with experimental data on the ∆G of ion pairs and shown to be in reasonable agreement. A general thermodynamic cycle for coupled ion transfer has been constructed to further elucidate facilitated ion permeation between water and membrane phases. Molecular interpretations of the results and their implications for various mechanisms of energy transduction have been discussed. We firmly believe that use of electrostatic theories such as the KTW theory that properly include the desolvation free energy penalty arising from the self-energy of the relevant ions are crucial for quantifying charge transfer processes in bioenergetics. Finally, the clear-cut implication is that proton-only and single-ion theories of ATP synthesis, such as the chemiosmotic theory, are grossly inadequate to comprehend energy storage and transduction in biological processes.