Insight into the K channel's selectivity from binding of K+, Na+ and water to N-methylacetamide.

In potassium channels that conduct K+ selectively over Na+, which sites are occupied by K+ or water and the mechanism of selectivity are unresolved questions. The combination of the energetics and the constraints imposed by the protein structure yield the selective permeation and occupancy. To gain insight into the combination of structure and energetics, we performed density functional theory (DFT) calculations of multiple N-methyl acetamide (NMA) ligands binding to K+ and Na+, relative to hydrated K+ and Na+. NMA is an analogue of the amino acid backbone and provides the carbonyl binding to the ions that occurs in most binding sites of the K+ channel. Unconstrained optimal structures are obtained through geometry optimization calculations of the NMA ligand binding. The complexes formed by 8 NMA binding to the cations have the O atoms positioned in nearly identical locations as the O atoms in the selectivity filter. The transfer free energies between bulk water and K+ or Na+ bound to 8 NMA are almost identical, implying there is no selectivity by a single site. For water optimized with 8 NMA, binding is weak and O atoms are not positioned as in the K+ channel selectivity filter, suggesting that the ions are much more favored than water. Optimal structures of 8 NMA binding with two cations (K+ or Na+) are stable and have lower binding free energy than the optimal structures with just one cation. However, in the Na+ case, the optimal structure deforms and does not match the K+ channel; that is, two bound Na+ are destabilizing. In contrast, the two K+ structure is stabilized and the selectivity free energy favors K+. Overall, this study shows that binding site occupancy and the mechanism for K+ selectivity involves multiple K+ binding in multiple neighboring layers or sites of the K+ channel selectivity filter.

Binding of Li+ to Negatively Charged and Neutral Ligands in Polymer Electrolytes.

Conceptually, single-ion polymer electrolytes (SIPE) with the anion bound to the polymer could solve major issues in Li-ion batteries, but their conductivity is too low. Experimentally, weakly interacting anionic groups have the best conductivity. To provide a theoretical basis for this result, density functional theory calculations of the optimized geometries and energies are performed for charged ligands used in SIPE. Comparison is made to neutral ligands found in dual-ion conductors, which demonstrate higher conductivity. The free energy differences between adding and subtracting a ligand are small enough for the neutral ligands to have the conductivity seen experimentally. However, charged ligands have large barriers, implying that lithium transport will coincide with the slow polymer diffusion, as observed in experiments. Overall, SIPE will require additional solvent to achieve a sufficiently high conductivity. Additionally, the binding of mono- and bidentate geometries varies, providing a simple and clear reason that polarizable force fields are required for detailed interactions.

Binding of carboxylate and water to monovalent cations.

The interactions of carboxylate anions with water and cations are important for a wide variety of systems, both biological and synthetic. To gain insight on properties of the local complexes, we apply density functional theory, to treat the complex electrostatic interactions, and investigate mixtures with varied numbers of carboxylate anions (acetate) and waters binding to monovalent cations, Li+, Na+ and K+. The optimal structure with overall lowest free energy contains two acetates and two waters such that the cation is four-fold coordinated, similar to structures found earlier for pure water or pure carboxylate ligands. More generally, the complexes with two acetates have the lowest free energy. In transitioning from the overall optimal state, exchanging an acetate for water has a lower free energy barrier than exchanging water for an acetate. In most cases, the carboxylates are monodentate and in the first solvation shell. As water is added to the system, hydrogen bonding between waters and carboxylate O atoms further stabilizes monodentate structures. These structures, which have strong electrostatic interactions that involve hydrogen bonds of varying strength, are significantly polarized, with ChelpG partial charges that vary substantially as the bonding geometry varies. Overall, these results emphasize the increasing importance of water as a component of binding sites as the number of ligands increases, thus affecting the preferential solvation of specific metal ions and clarifying Hofmeister effects. Finally, structural analysis correlated with free energy analysis supports the idea that binding to more than the preferred number of carboxylates under architectural constraints are a key to ion transport.

Carboxylate binding prefers two cations to one.

Almost all studies of specific ion binding by carboxylates (-COO-) have considered only a single cation, but clustering of ions and ligands is a common phenomenon. We apply density functional theory to investigate how variations in the number of acetate ligands in binding to two monovalent cations affects ion binding preferences. We study a series of monovalent (Li+, Na+, K+, Cs+) ions relevant to experimental work on many topics, including ion channels, battery storage, water purification and solar cells. We find that the preferred optimal structure has 3 acetates except for Cs+, which has 2 acetates. The optimal coordination of the cation by the carboxylate O atoms is 4 for both Na+ and K+, and 3 for Li+ and Cs+. There is a 4-fold coordination minimum just a few kcal mol-1 higher than the optimal 3-fold structure for Li+. For two cations, multiple minima occur in the vicinity of the lowest free energy state. We find that, for Li, Na and K, the preferred optimal structure with two cations is favored over a mixture of single cation complexes, providing a basis for understanding ionic cluster formation that is relevant for engineering proteins and other materials for rapid, selective ion transport.

Trapping Ca+ inside a molecular cavity: computational study of the potential energy surfaces for Ca+-[n]cycloparaphenylene, n = 5-12.

Ion trap quantum computing utilizes electronic states of atomic ions such as Ca+ to encode information on to a qubit. To explore the fundamental properties of Ca+ inside molecular cavities, we describe here a computational study of Ca+ bound inside neutral [n]-cycloparaphenylenes (n = 5-12), often referred to as "nanohoops". This ab initio study characterizes optimized structures, harmonic vibrational frequencies, potential energy surfaces, and ion molecular orbital distortion as functions of increasing nanohoop size. The results of this work provide a first step in guiding experimental studies of the spectroscopy of these ion-molecular cavity complexes.

Ion-Specific Effects in Carboxylate Binding Sites.

Specific ion binding by carboxylates (-COO-) is a broadly important topic because -COO- is one of the most common functional groups coordinated to metal ions in metalloproteins and synthetic polymers. We apply quantum chemical methods and the quasi-chemical free-energy theory to investigate how variations in the number of -COO- ligands in a binding site determine ion-binding preferences. We study a series of monovalent (Li+, Na+, K+, Cs+) and divalent (Zn2+, Ca2+) ions relevant to experimental work on ion channels and ionomers. Of two competing hypotheses, our results support the ligand field strength hypothesis and follow the reverse Hofmeister series for ion solvation and ion transfer from aqueous solution to binding sites with the preferred number of ligands. New insight arises from the finding that ion-binding sequences can be manipulated and even reversed just by constraining the number of carboxylate ligands in the binding sites. Our results help clarify the discrepancy in ion association between molecular ligands in aqueous solutions and ionomers, and their chemical analogues in ion-channel binding sites.

Computing the 7Li NMR chemical shielding of hydrated Li+ using cluster calculations and time-averaged configurations from ab initio molecular dynamics simulations.

Ab initio molecular dynamics (AIMD) simulations have been used to predict the time-averaged Li NMR chemical shielding for a Li(+) solution. These results are compared to NMR shielding calculations on smaller Li(+)(H(2)O)(n) clusters optimized in either the gas phase or with a polarizable continuum model (PCM) solvent. The trends introduced by the PCM solvent are described and compared to the time-averaged chemical shielding observed in the AIMD simulations where large explicit water clusters hydrating the Li(+) are employed. Different inner- and outer-coordination sphere contributions to the Li NMR shielding are evaluated and discussed. It is demonstrated an implicit PCM solvent is not sufficient to correctly model the Li shielding, and that explicit inner hydration sphere waters are required during the NMR calculations. It is also shown that for hydrated Li(+), the time averaged chemical shielding cannot be simply described by the population-weighted average of coordination environments containing different number of waters.