Two mechanisms of ion selectivity in protein binding sites

Abstract

A theoretical framework is presented to clarify the molecular determinants of ion selectivity in protein binding sites. The relative free energy of a bound ion is expressed in terms of the main coordinating ligands coupled to an effective potential of mean force representing the influence of the rest of the protein. The latter is separated into two main contributions. The first includes all the forces keeping the ion and the coordinating ligands confined to a microscopic subvolume but does not prevent the ligands from adapting to a smaller or larger ion. The second regroups all the remaining forces that control the precise geometry of the coordinating ligands best adapted to a given ion. The theoretical framework makes it possible to delineate two important limiting cases. In the limit where the geometric forces are dominant (rigid binding site), ion selectivity is controlled by the ion-ligand interactions within the matching cavity size according to the familiar "snugfit" mechanism of host-guest chemistry. In the limit where the geometric forces are negligible, the ion and ligands behave as a "confined microdroplet" that is free to fluctuate and adapt to ions of different sizes. In this case, ion selectivity is set by the interplay between ion-ligand and ligand-ligand interactions and is controlled by the number and the chemical type of ion-coordinating ligands. The framework is illustrated by considering the ion-selective binding sites in the KcsA channel and the LeuT transporter.computations | free energy | ion coordination | KcsA | LeuT

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“…That the pore helix acts to integrate multiple allosteric inputs that influence the state of the selectivity filter is entirely consistent with our previous suggestion that inactivation gating is analogous to the opening and closing of a Japanese puzzle box (13). A dynamic role for the pore helix is also consistent with recent molecular dynamics studies indicating that ion selectivity is not dependent on static selectivity filter structures (52). Although our work has focused on the Kv11.1 channel, there is no doubt that the pore helix plays a critical role in inactivation gating in all channels.…”

The Two Na+ Sites in the Human Serotonin Transporter Play Distinct Roles in the Ion Coupling and Electrogenicity of Transport

“…Recent computational analysis of the Na2 binding site in proteins with the LeuT-fold predicted that transition to an inward facing conformation destabilizes Na ϩ coordination at Na2, resulting in Na ϩ release followed by substrate dissociation (19,(35)(36)(37)(38)(39)(40). Were this true in hSERT, which appears to translocate a single Na ϩ per transport cycle, the cation at Na1 would not be mobile.…”

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