title: Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state.
abstract: The selectivity filter of K+ channels provides specific coordinative interactions between dipolar carbonyl ligands, water, and the permeant cation, which allow for selective flow of K+ over (most importantly) Na+ across the cell membrane. Although a structural viewpoint attributes K+ selectivity to coordination geometry provided by the filter, recent molecular dynamics simulation studies attribute it to dynamic and unique chemical/electrostatic properties of the filter's carbonyl ligands. Here we provide a simple theoretical analysis of K+ and Na+ complexation with water in the context of simplified binding site models and bulk solution. Our analysis reveals that water molecules and carbonyl groups can both provide K+ selective environments if equivalent constraints are imposed on the coordination number of the complex. Absence of such constraints annihilates selectivity, demonstrating that whether a coordinating ligand is a water molecule or a carbonyl group, "external" or "topological" constraints/forces must be imposed on an ion-coordinated complex to elicit selective binding. These forces must inevitably originate from the channel protein, because in bulk water, which, by definition, presents a nonselective medium, the coordination number is allowed to relax to suit the ion. We show that the coordination geometry of K+ channel binding sites is replicated by 8-fold complexation of K+ in both water and simplified binding site models due to dominance of local interactions within a complex and is thus a requirement for topologically constraining the coordination number to a specific value.
authors.affiliation: Department of Molecular Biology and Center for Theoretical Biological Physics, The Scripps Research Institute, 10550 North Torrey Pines Road, TPC 6, La Jolla, CA 92037, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bostick
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D007477:Ions / Q000737:chemistry*; D008954:Models, Biological; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D014867:Water
chemical_list: D007477:Ions; D015221:Potassium Channels; D014867:Water