Susan B. Rempe

The Hydration Number of Li+ in Liquid Water

The hydration of ions in water is not only fundamental to physical chemistry, but is also relevant to the current issue of selectivity of biological ion channels. In the context of potassium channels for example, the free energies for replacement of inner shell water ligands with peptide carbonyls donated by proteins of the channel, specifically for the preference of K{sup +} over Na{sup +}. Studies to elucidate the thermodynamic features of such inner shell exchange reactions require prior knowledge of the ion hydration structures and energetics. Simulations have produced a range of results including both four and six inner shell water neighbors with considerable statistical dispersion. Simulations are typically not designed to provide sole determinations of such properties, although they do shed light on the issues determining the hydration number of ions in water. The theoretical scheme used here to address these problems for the Li{sup +}(aq) ion is based upon the quasi-chemical organization of solution theory, which is naturally suited to these problems.

Ab initio molecular dynamics study of glycine intramolecular proton transfer in water

We use ab initio molecular-dynamics simulations to quantify structural and thermodynamic properties of a model proton transfer reaction that converts a neutral glycine molecule, stable in the gas phase, to the zwitterion that predominates in aqueous solution. We compute the potential of mean force associated with the direct intramolecular proton transfer event in glycine. Structural analyses show that the average hydration number (N(w)) of glycine is not constant along the reaction coordinate, but rather progresses from N(w) = 5 in the neutral molecule to N(w) = 8 for the zwitterion. We report the free-energy difference between the neutral and charged glycine molecules, and the free-energy barrier to proton transfer. Finally, we identify the approximations inherent in our method and estimate the corresponding corrections to our reported thermodynamic predictions.

Modeling Electrochemical Decomposition of Fluoroethylene Carbonate on Silicon Anode Surfaces in Lithium Ion Batteries

Fluoroethylene carbonate (FEC) shows promise as an electrolyte additive for improving passivating solid-electrolyte interphase (SEI) films on silicon anodes used in lithium ion batteries (LIB). We apply density functional theory (DFT), ab initio molecular dynamics (AIMD), and quantum chemistry techniques to examine excess-electron-induced FEC molecular decomposition mechanisms that lead to FEC-modified SEI. We consider one- and two-electron reactions using cluster models and explicit interfaces between liquid electrolyte and model Li(x)Si(y) surfaces, respectively. FEC is found to exhibit more varied reaction pathways than unsubstituted ethylene carbonate. The initial bond-breaking events and products of one- and two-electron reactions are qualitatively similar, with a fluoride ion detached in both cases. However, most one-electron products are charge-neutral, not anionic, and may not coalesce to form effective Li+-conducting SEI unless they are further reduced or take part in other reactions. The implications of these reactions to silicon-anode based LIB are discussed.

The glutaminase activity of L- Asparaginase is not required for anticancer activity against ASNS-negative cells

L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASPs glutaminase activity is not always required for the enzymes anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type L-ASP for ASNS-negative cancers.

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

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 overcoordinated 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.

Inner shell definition and absolute hydration free energy of K+(aq) on the basis of quasi-chemical theory and ab initio molecular dynamics

The K+(aq) ion is an integral component of many cellular processes, amongst which the most important, perhaps, is its role in transmitting electrical impulses along the nerve. Understanding its hydration structure and thermodynamics is crucial in dissecting its role in such processes. Here we address these questions using both the statistical mechanical quasi-chemical theory of solutions and ab initio molecular dynamics simulations. Simulations predict an interesting hydration structure for K+(aq): the population of about six (6) water molecules within the initial minimum of the observed gKO(r) at infinite dilution involves four (4) innermost molecules that the quasi-chemical theory suggests should be taken as the theoretical inner shell. The contribution of the fifth and sixth closest water molecules is observable as a distinct shoulder on the principal maximum of the gKO(r). The quasi-chemical estimate of solvation free energy for the neutral pair KOH is also in good agreement with experiments.

Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport.

Selection among competing alternatives is always interesting, but when organisms select between K+ and Na+ for transport across biological membranes, it is especially intriguing for a couple of reasons (Hille, 2001). First, the results are physiologically significant. Second, K+ and Na+ are nearly as similar as they could be while not being the same things. Perhaps the separation of isotopes of the same chemical species is more demanding. Despite decades of research, the question remains: how do K+-selective ion channels catalyze K+ movement but recognize the detailed molecular-scale differences of Na+ and discriminate against it? Suggestions based on channel size and coordination chemistry (Bezanilla and Armstrong, 1972; Eisenman and Horn, 1983) have been available for a long time, but the determination of a KcsA K+ channel crystal structure (Doyle et al., 1998) enabled molecularly specific modeling studies of this K+/Na+ selectivity. In the subsequent flood of computational studies, finding consistency in results and interpretations has proven challenging. Here, we describe our perspective on how molecular modeling has advanced our understanding of the specific chemical and structural design elements of biological molecules that enable selective ion transport.

Interactions and structure of poly(dimethylsiloxane) at silicon dioxide surfaces: Electronic structure and molecular dynamics studies

Electronic structure studies are used to probe the interactions and molecular dynamics simulations are used to study the structure of thin poly(dimethylsiloxane) (PDMS) films near hydroxylated SiO2 substrates. Results of the electronic structure calculations show that the PDMS end groups, rather than atoms such as oxygen in the PDMS backbone structure, dominate interactions at the interface. Methyl–terminated PDMS binds weakly with the substrate via interactions between H atoms on PDMS methyl groups and O atoms on the substrate hydroxyl groups, while hydroxyl–terminated PDMS binds strongly with the substrate via hydrogen bonding between hydroxyl groups on PDMS and the substrate. To study the effect of temperature and type of substrate on the structural ordering of the PDMS liquid near the solid/liquid and liquid/air interfaces, molecular dynamics simulations for two temperatures (300 and 400 K) are carried out for three hydroxylated SiO2 substrates (α–quartz, β–cristobalite and amorphous SiO2). A direct c...

Quasi-chemical theory and implicit solvent models for simulations

A statistical thermodynamic development is given of a new implicit solvent model that avoids the traditional system size limitations of computer simulation of macromolecular solutions with periodic boundary conditions. This implicit solvent model is based upon the quasi-chemical approach, distinct from the common integral equation trunk of the theory of liquid solutions. The idea is geometrically to define molecular-scale regions attached to the solute macromolecule of interest. It is then shown that the quasi-chemical approach corresponds to calculation of a partition function for an ensemble analogous to, but not the same as, the grand canonical ensemble for the solvent in that proximal volume. The distinctions include: (a) the defined proximal volume—the volume of the system that is treated explicitly—resides on the solute; (b) the solute conformational fluctuations are prescribed by statistical thermodynamics and the proximal volume can fluctuate if the solute conformation fluctuates; and (c) the inte...

Multibody Effects in Ion Binding and Selectivity

Selective binding of ions to biomolecules plays a vital role in numerous biological processes. To understand the specific role of induced effects in selective ion binding, we use quantum chemical and pairwise-additive force-field simulations to study Na(+) and K(+) binding to various small molecules representative of ion binding functional groups in biomolecules. These studies indicate that electronic polarization significantly contributes to both absolute and relative ion-binding affinities. Furthermore, this contribution depends on both the number and the specific chemistries of the coordinating molecules, thus highlighting the complexity of ion-ligand interactions. Specifically, multibody interactions reduce as well as enhance the dipole moments of the ion-coordinating molecules, thereby affecting observables like coordination number distributions of ions. The differential polarization induced in molecules coordinating these two equivalently charged, but different-sized, ions also depends upon the number of coordinating molecules, showing the importance of multibody effects in distinguishing these ions thermodynamically. Because even small differences in ionic radii (0.4 Å for Na(+) and K(+)) produce differential polarization trends critical to distinguishing ions thermodynamically, it is likely that polarization plays an important role in thermodynamically distinguishing other ions and charged chemical and biological functional groups.