Structural Transitions in Ion Coordination Driven by Changes in Competition for Ligand Binding

Abstract

Transferring Na + and K + ions from their preferred coordination states in water to states having different coordination numbers incurs a free energy cost. In several examples in nature, however, these ions readily partition from aqueous-phase coordination states into spatial regions having much higher coordination numbers. Here we utilize statistical theory of solutions, quantum chemical simulations, classical mechanics simulations and structural informatics to understand this aspect of ion partitioning. Our studies lead to the identification of a specific role of the solvation environment in driving transitions in ion coordination structures. Although ion solvation in liquid media is an exergonic reaction overall, we find it is also associated with considerable free energy penalties for extracting ligands from their solvation environments to form coordinated ion complexes. Reducing these penalties increases the stabilities of higher-order coordinations and brings down the energetic cost to partition ions from water into over-coordinated binding sites in biomolecules. These penalties can be lowered via a reduction in direct favorable interactions of the coordinating ligands with all atoms other than the ions themselves. A significant reduction in these penalties can, in fact, also drive up ion coordination preferences. Similarly, an increase in these penalties can lower ion coordination preferences, akin to a Hofmeister effect. Since such structural transitions are effected by the properties of the solvation phase, we anticipate that they will also occur for other ions. The influence of other factors, including ligand density, ligand chemistry and temperature, on the stabilities of ion coordination structures are also explored.

Role of methyl-induced polarization in ion binding

“…The presence of other polar chemical moieties proximal to the S4 site, including water molecules, can reduce the contribution of polarization, and thereby the overall effect of T→S substitutions on Ba 2+ binding. Thermodynamically, this reduction will appear as an increase in the free energy penalty associated with threonine extraction from its local environment, which has been shown to influence ion binding (40,41). Another possible explanation could be that the computed values may not be comparable directly with experimental estimates.…”

“…We use the "tight" settings for integration grids and basis sets, as described by Blum et al (57), which yield converged energy differences and negligible basis set superposition error. The starting geometries of the ion-water complexes are taken from the work of Varma and Rempe (41), and the starting geometries of the ionalcohol complexes are constructed using the ion-water complexes as templates.…”

Assessing the accuracy of approximate treatments of ion hydration based on primitive quasichemical theory

“…In view of these limitations, it appears that the conclusions of previous pQCT studies that have sought to explain ion selectivity in protein binding sites primarily in terms of coordination numbers may need to be reassessed. 15,16 Interestingly, the inaccuracy in P i ͑n͒ does not considerably affect the magnitude of the hydration free energies. As first noted by Merchant and Asthagiri,11 this is explained by the thermodynamic dominance of the low coordination number contributions to ⌬G i .…”

“…This strategy has been used to examine the hydration of Li + , Na + , and K + . [12][13][14] pQCT has also been employed to discuss ion selectivity in proteins' binding sites, 15,16 but as it is a framework strictly designed to treat ion solvation in a bulk liquid, the significance of those studies is less clear.…”

Polarization and charge transfer in the hydration of chloride ions

“…The quasi-chemical treatment of solvation thermodynamics provides a natural statistical mechanical framework for representing the first solvation shell at an accurate quantum mechanical level, with a lower-level representation of more distant waters. 86,87,88 …”