title: Exploring the ion selectivity properties of a large number of simplified binding site models.
abstract: The ability to discriminate between different cations efficiently is essential for the proper physiological functioning of many membrane transport proteins. One obvious mechanism of ion selectivity is when a binding site is structurally constrained by the protein architecture and its geometry is precisely adapted to fit an ion of a given size. This mechanism is not effective in the case of flexible protein binding sites that are able to deform structurally or to adapt to a bound ion. In this study, the concept of nontrivial ion selectivity arising in a highly flexible protein binding site conceptually represented as a microdroplet of ligands confined to a small volume is explored. The environment imposed by the spatial confinement is a critical feature of the reduced models. A large number of reduced binding site models (1077) comprising typical ion-coordinating ligands (carbonyl, hydroxyl, carboxylate, water) are constructed and characterized for Na(+)/K(+) and Ca(2+)/Ba(2+) size selectivity using free energy perturbation molecular dynamics simulations. Free energies are highly correlated with the sum of ion-ligand and ligand-ligand mean interactions, but the relative balance of those two contributions is different for K(+)-selective and Na(+)-selective binding sites. The analysis indicates that both the number and the type of ligands are important factors in ion selectivity.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA. roux@uchicago.edu
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
mesh_terms: D001665:Binding Sites; D006033:Glycylglycine / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D008024:Ligands; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D007477:Ions; D008024:Ligands; D026901:Membrane Transport Proteins; D006033:Glycylglycine; D010100:Oxygen