Interacting ions in biophysics: real is not ideal

Ions in water are important throughout biology, from molecules to organs. Classically, ions in water were treated as ideal noninteracting particles in a perfect gas. Excess free energy of each ion was zero. Mathematics was not available to deal consistently with flows, or interactions with other ions or boundaries. Nonclassical approaches are needed because ions in biological conditions flow and interact. The concentration gradient of one ion can drive the flow of another, even in a bulk solution. A variational multiscale approach is needed to deal with interactions and flow. The recently developed energetic variational approach to dissipative systems allows mathematically consistent treatment of the bio-ions Na(+), K(+), Ca(2+), and Cl(-) as they interact and flow. Interactions produce large excess free energy that dominate the properties of the high concentration of ions in and near protein active sites, ion channels, and nucleic acids: the number density of ions is often >10 M. Ions in such crowded quarters interact strongly with each other as well as with the surrounding protein. Nonideal behavior found in many experiments has classically been ascribed to allosteric interactions mediated by the protein and its conformation changes. The ion-ion interactions present in crowded solutions-independent of conformation changes of the protein-are likely to change the interpretation of many allosteric phenomena. Computation of all atoms is a popular alternative to the multiscale approach. Such computations involve formidable challenges. Biological systems exist on very different scales from atomic motion. Biological systems exist in ionic mixtures (like extracellular and intracellular solutions), and usually involve flow and trace concentrations of messenger ions (e.g., 10(-7) M Ca(2+)). Energetic variational methods can deal with these characteristic properties of biological systems as we await the maturation and calibration of all-atom simulations of ionic mixtures and divalents.