Hydration Structure of Na+ and K+ Ions in Solution Predicted by Data-Driven Many-Body Potentials.

The hydration structure of Na+ and K+ ions in solution is systematically investigated using a hierarchy of molecular models that progressively include more accurate representations of many-body interactions. We found that a conventional empirical pairwise additive force field that is commonly used in biomolecular simulations is unable to reproduce the extended X-ray absorption fine structure (EXAFS) spectra for both ions. In contrast, progressive inclusion of many-body effects rigorously derived from the many-body expansion of the energy allows the MB-nrg potential energy functions (PEFs) to achieve nearly quantitative agreement with the experimental EXAFS spectra, thus enabling the development of a molecular-level picture of the hydration structure of both Na+ and K+ in solution. Since the MB-nrg PEFs have already been shown to accurately describe isomeric equilibria and vibrational spectra of small ion-water clusters in the gas phase, the present study demonstrates that the MB-nrg PEFs effectively represent the long-sought-after models able to correctly predict the properties of ionic aqueous systems from the gas to the liquid phase, which has so far remained elusive.

Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling.

Sodium ions are endogenous allosteric modulators of many G-protein-coupled receptors (GPCRs). Mutation of key residues in the sodium binding motif causes a striking effect on G-protein signaling. We report the crystal structures of agonist complexes for two variants in the first sodium coordination shell of the human A2A adenosine receptor, D522.50N and S913.39A. Both structures present an overall active-like conformation; however, the variants show key changes in the activation motif NPxxY. Changes in the hydrogen bonding network in this microswitch suggest a possible mechanism for modified G-protein signaling and enhanced thermal stability. These structures, signaling data, and thermal stability analysis with a panel of pharmacological ligands provide a basis for understanding the role of the sodium-coordinating residues on stability and G-protein signaling. Utilizing the D2.50N variant is a promising method for stabilizing class A GPCRs to accelerate structural efforts and drug discovery.