Inner and Outer Coordination Shells of Mg<sup>2+</sup> in CorA Selectivity Filter from Molecular Dynamics Simulations

Structural data of CorA Mg<sup>2+</sup> channels show that the five Gly-Met-Asn (GMN) motifs at the periplasmic loop of the pentamer structure form a molecular scaffold serving as a selectivity filter. Unfortunately, knowledge about the cation selectivity of Mg<sup>2+</sup> channels remains limited. Since Mg<sup>2+</sup> in aqueous solution has a strong first hydration shell and apparent second hydration sphere, the coordination structure of Mg<sup>2+</sup> in a CorA selectivity filter is expected to be different from that in bulk water. Hence, this study investigated the hydration structure and ligand coordination of Mg<sup>2+</sup> in a selectivity filter of CorA using molecular dynamics (MD) simulations. The simulations reveal that the inner-shell structure of Mg<sup>2+</sup> in the filter is not significantly different from that in aqueous solution. The major difference is the characteristic structural features of the outer shell. The GMN residues engage indirectly in the interactions with the metal ion as ligands in the second shell of Mg<sup>2+</sup>. Loss of hydrogen bonds between inner- and outer-shell waters observed from Mg<sup>2+</sup> in bulk water is mostly compensated by interactions between waters in the first solvation shell and the GMN motif. Some water molecules in the second shell remain in the selectivity filter and become less mobile to support the metal binding. Removal of Mg<sup>2+</sup> from the divalent cation sensor sites of the protein had an impact on the structure and metal binding of the filter. From the results, it can be concluded that the GMN motif enhances the affinity of the metal binding site in the CorA selectivity filter by acting as an outer coordination ligand.