Publications

Rare-earth metals (REMs) are crucial for many important industries, such as power generation and storage, in addition to cancer treatment and medical imaging. One promising new REM refinement approach involves mimicking the highly selective and efficient binding of REMs observed in relatively recently discovered proteins. However, realizing any such bioinspired approach requires an understanding of the biological recognition mechanisms. In this report we developed a new classical polarizable force field based on the AMOEBA framework for modeling a lanthanum ion (La³⁺) interacting with water, acetate, and acetamide, which have been found to coordinate the ion in proteins. The parameters were derived by comparing to high-level ab initio quantum mechanical (QM) calculations that include relativistic effects. The AMOEBA model, with advanced atomic multipoles and electronic polarization, is successful in capturing both the QM distance-dependent La³⁺–ligand interaction energies and experimental hydration free energy. A new scheme for pairwise polarization damping (POLPAIR) was developed to describe the polarization energy in La³⁺ interactions with both charged and neutral ligands. Simulations of La3+ in water showed water coordination numbers and ion–water distances consistent with previous experimental and theoretical findings. Water residence time analysis revealed both fast and slow kinetics in water exchange around the ion. This new model will allow investigation of fully solvated lanthanum ion–protein systems using GPU-accelerated dynamics simulations to gain insights on binding selectivity, which may be applied to the design of synthetic analogues.

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.

ConspectusThe interactions of hydrated ions with molecular and macromolecular solution and interface partners are strong on a chemical energy scale. Here, we recount the foremost ab initio theory for the evaluation of the hydration free energies of ions, namely, quasi-chemical theory (QCT). We focus on anions, particularly halides but also the hydroxide anion, because they have been outstanding challenges for all theories. For example, this work supports understanding the high selectivity for F-over Cl-in fluoride-selective ion channels despite the identical charge and the size similarity of these ions. QCT is built by the identification of inner-shell clusters, separate treatment of those clusters, and then the integration of those results into the broader-scale solution environment. Recent work has focused on a close comparison with mass-spectrometric measurements of ion-hydration equilibria. We delineate how ab initio molecular dynamics (AIMD) calculations on ion-hydration clusters, elementary statistical thermodynamics, and electronic structure calculations on cluster structures sampled from the AIMD calculations obtain just the free energies extracted from the cluster experiments. That theory-experiment comparison has not been attempted before the work discussed here, but the agreement is excellent with moderate computational effort. This agreement reinforces both theory and experiment and provides a numerically accurate inner-shell contribution to QCT. The inner-shell complexes involving heavier halides display strikingly asymmetric hydration clusters. Asymmetric hydration structures can be problematic for the evaluation of the QCT outer-shell contribution with the polarizable continuum model (PCM). Nevertheless, QCT provides a favorable setting for the exploitation of PCM when the inner-shell material shields the ion from the outer solution environment. For the more asymmetrically hydrated, and thus less effectively shielded, heavier halide ions clustered with waters, the PCM is less satisfactory. We therefore investigate an inverse procedure in which the inner-shell structures are sampled from readily available AIMD calculations on the bulk solutions. This inverse procedure is a remarkable improvement; our final results are in close agreement with a standard tabulation of hydration free energies, and the final composite results are independent of the coordination number on the chemical energy scale of relevance, as they should be. Finally, a comparison of anion hydration structure in clusters and bulk solutions from AIMD simulations emphasize some differences: the asymmetries of bulk solution inner-shell structures are moderated compared with clusters but are still present, and inner hydration shells fill to slightly higher average coordination numbers in bulk solution than in clusters.

Abstract not provided.

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.

Organophosphorus hydrolase (OPH) is a metalloenzyme that can hydrolyze organophosphorus agents resulting in products that are generally of reduced toxicity. The best OPH substrate found to date is diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we used a combined docking and molecular dynamics (MD) approach to predict the likely binding mode of paraoxon. Then, we used the predicted binding mode to run MD simulations on the wild type (WT) OPH complexed with paraoxon, and OPH mutants complexed with paraoxon. Additionally, we identified three hot-spot residues (D253, H254, and I255) involved in the stability of the OPH active site. We then experimentally assayed single and double mutants involving these residues for paraoxon binding affinity. The binding free energy calculations and the experimental kinetics of the reactions between each OPH mutant and paraoxon show that mutated forms D253E, D253E-H254R, and D253E-I255G exhibit enhanced substrate binding affinity over WT OPH. Interestingly, our experimental results show that the substrate binding affinity of the double mutant D253E-H254R increased by 19-fold compared to WT OPH.

The objective of this project was to eliminate and/or render bulk agent unusable by a threat entity via neutralization and/or polymerization of the bulk agent using minimal quantities of additives. We proposed the in situ neutralization and polymerization of bulk chemical agents (CAs) by performing reactions in the existing CA storage container via wet chemical approaches using minimal quantities of chemical based materials. This approach does not require sophisticated equipment, fuel to power generators, electricity to power equipment, or large quantities of decontaminating materials. By utilizing the CA storage container as the batch reactor, the amount of logistical resources can be significantly reduced. Fewer personnel are required since no sophisticated equipment needs to be set up, configured, or operated. Employing the CA storage container as the batch reactor enables the capability to add materials to multiple containers in a short period of time as opposed to processing one container at a time for typical batch reactor approaches. In scenarios where a quick response is required, the material can be added to all the CA containers and left to react on its own without intervention. Any attempt to filter the CA plus material solution will increase the rate of reaction due to increased agitation of the solution.

Recently, lithium nitride (Li3N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li3N neutralization process that has been studied experimentally. Here, we calculate reaction-free energies associated with the Li3N-based neutralization of the CWA VX using quantum chemical density functional theory and ab initio methods. We find that alkaline hydrolysis is more favorable to either ammonolysis or neutral hydrolysis for initial P-S and P-O bond cleavages. Reaction-free energies of subsequent reactions are calculated to determine the full reaction pathway. Notably, products predicted from favorable reactions have been identified in previous experiments.

Abstract not provided.

The addition of a common amino acid, phenylalanine, to a Layer-by-Layer (LbL) deposited polyelectrolyte (PE) film on a nanoporous membrane can increase its ionic selectivity over a PE film without the added amino acid. The addition of phenylalanine is inspired by detailed knowledge of the structure of the channelrhodopsins family of protein ion channels, where phenylalanine plays an instrumental role in facilitating sodium ion transport. The normally deposited and crosslinked PE films increase the cationic selectivity of a support membrane in a controllable manner where higher selectivity is achieved with thicker PE coatings, which in turn also increases the ionic resistance of the membrane. The increased ionic selectivity is desired while the increased resistance is not. We show that through incorporation of phenylalanine during the LbL deposition process, in solutions of NaCl with concentrations ranging from 0.1 to 100 mM, the ionic selectivity can be increased independently of the membrane resistance. Specifically, the addition is shown to increase the cationic transference of the PE films from 81.4% to 86.4%, an increase on par with PE films that are nearly triple the thickness while exhibiting much lower resistance compared to the thicker coatings, where the phenylalanine incorporated PE films display an area specific resistance of 1.81 Ω cm2in 100 mM NaCl while much thicker PE membranes show a higher resistance of 2.75 Ω cm2in the same 100 mM NaCl solution.

Potassium channels modulate various cellular functions through efficient and selective conduction of K+ions. The mechanism of ion conduction in potassium channels has recently emerged as a topic of debate. Crystal structures of potassium channels show four K+ions bound to adjacent binding sites in the selectivity filter, while chemical intuition and molecular modeling suggest that the direct ion contacts are unstable. Molecular dynamics (MD) simulations have been instrumental in the study of conduction and gating mechanisms of ion channels. Based on MD simulations, two hypotheses have been proposed, in which the four-ion configuration is an artifact due to either averaged structures or low temperature in crystallographic experiments. The two hypotheses have been supported or challenged by different experiments. Here, MD simulations with polarizable force fields validated byab initiocalculations were used to investigate the ion binding thermodynamics. Contrary to previous beliefs, the four-ion configuration was predicted to be thermodynamically stable after accounting for the complex electrostatic interactions and dielectric screening. Polarization plays a critical role in the thermodynamic stabilities. As a result, the ion conduction likely operates through a simple single-vacancy and water-free mechanism. The simulations explained crystal structures, ion binding experiments and recent controversial mutagenesis experiments. This work provides a clear view of the mechanism underlying the efficient ion conduction and demonstrates the importance of polarization in ion channel simulations.

With a longer-term goal of addressing the comparative behavior of the aqueous halides F-, Cl-, Br-, and I-on the basis of quasi-chemical theory (QCT), here we study structures and free energies of hydration clusters for those anions. We confirm that energetically optimal (H2O)nX clusters, with X = Cl-, Br-, and I-, exhibit surface hydration structures. Computed free energies, based on optimized surface hydration structures utilizing a harmonic approximation, typically (but not always) disagree with experimental free energies. To remedy the harmonic approximation, we utilize single-point electronic structure calculations on cluster geometries sampled from an AIMD (ab initio molecular dynamics) simulation stream. This rough-landscape procedure is broadly satisfactory and suggests unfavorable ligand crowding as the physical effect addressed. Nevertheless, this procedure can break down when n≳4, with the characteristic discrepancy resulting from a relaxed definition of clustering in the identification of (H2O)nX clusters, including ramified structures natural in physical cluster theories. With ramified structures, the central equation for the present rough-landscape approach can acquire some inconsistency. Extension of these physical cluster theories in the direction of QCT should remedy that issue, and should be the next step in this research direction.

Lawrence Pratt’s career following completion of his Ph.D. at the University of Illinois Urbana Champaign has taken him from Harvard University, to the University of California, Berkeley, and Los Alamos National Laboratory. Most recently, he joined the faculty of the Department of Chemical and Biomolecular Engineering at Tulane University in 2008. Over his career Lawrence has been a leader in theoretical physical chemistry, making influential contributions to a number of areas including the theory of the hydrophobic effect, the development of transition path sampling, contributions to orbital free density functional theory, and the theory of liquids and solutions.

Channelrhodopsins (ChR) are light-sensitive cation channels used in optogenetics, a technique that applies light to control cells (e.g., neurons) that have been modified genetically to express those channels. Although mutations are known to affect pore kinetics, little is known about how mutations induce changes at the molecular scale. To address this issue, we first measured channel opening and closing rates of a ChR chimera (C1C2) and selected variants (N297D, N297V, and V125L). Then, we used atomistic simulations to correlate those rates with changes in pore structure, hydration, and chemical interactions among key gating residues of C1C2 in both closed and open states. Overall, the experimental results show that C1C2 and its mutants do not behave like ChR2 or its analogous variants, except V125L, making C1C2 a unique channel. Our atomistic simulations confirmed that opening of the channel and initial hydration of the gating regions between helices I, II, III, and VII of the channel occurs with 1) the presence of 13-cis retinal; 2) deprotonation of a glutamic acid gating residue, E129; and 3) subsequent weakening of the central gate hydrogen bond between the same glutamic acid E129 and asparagine N297 in the central region of the pore. Also, an aspartate (D292) is the unambiguous primary proton acceptor for the retinal Schiff base in the hydrated channel.

Electrodialysis (ED) desalination performance of different conventional and laboratoryscale ion exchange membranes (IEMs) has been evaluated by many researchers, but most of these studies used their own sets of experimental parameters such as feed solution compositions and concentrations, superficial velocities of the process streams (diluate, concentrate, and electrode rinse), applied electrical voltages, and types of IEMs. Thus, direct comparison of ED desalination performance of different IEMs is virtually impossible. While the use of different conventional IEMs in ED has been reported, the use of bioinspired ion exchange membrane has not been reported yet. The goal of this study was to evaluate the ED desalination performance differences between novel laboratory-scale bioinspired IEM and conventional IEMs by determining (i) limiting current density, (ii) current density, (iii) current efficiency, (iv) salinity reduction in diluate stream, (v) normalized specific energy consumption, and (vi) water flux by osmosis as a function of (a) initial concentration of NaCl feed solution (diluate and concentrate streams), (b) superficial velocity of feed solution, and (c) applied stack voltage per cell-pair of membranes. A laboratory-scale single stage batchrecycle electrodialysis experimental apparatus was assembled with five cell-pairs of IEMs with an active cross-sectional area of 7.84 cm2. In this study, seven combinations of IEMs (commercial and laboratory-made) were compared: (i) Neosepta AMX/CMX, (ii) PCA PCSA/PCSK, (iii) Fujifilm Type 1 AEM/CEM, (iv) SUEZ AR204SZRA/CR67HMR, (v) Ralex AMH-PES/CMH-PES, (vi) Neosepta AMX/Bare Polycarbonate membrane (Polycarb), and (vii) Neosepta AMX/Sandia novel bioinspired cation exchange membrane (SandiaCEM). ED desalination performance with the Sandia novel bioinspired cation exchange membrane (SandiaCEM) was found to be competitive with commercial Neosepta CMX cation exchange membrane.

The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for many classes of antibacterial agents. Lipopolysaccharide (LPS), present in the outer leaflet of the OM, is stabilized by divalent cations and is considered to be the major impediment for antibacterial agent permeation. However, the actual affinities of major antibiotic classes toward LPS have not yet been determined. In the present work, we use Langmuir monolayers formed from E. coli Re and Rd types of LPS to record pressure-area isotherms in the presence of antimicrobial agents. Our observations suggest three general types of interactions. First, some antimicrobials demonstrated no measurable interactions with LPS. This lack of interaction in the case of cefsulodin, a third-generation cephalosporin antibiotic, correlates with its low efficacy against G-bacteria. Ampicillin and ciprofloxacin also show no interactions with LPS, but in contrast to cefsulodin, both exhibit good efficacy against G-bacteria, indicating permeation through common porins. Second, we observe substantial intercalation of the more hydrophobic antibiotics, novobiocin, rifampicin, azithromycin, and telithromycin, into relaxed LPS monolayers. These largely repartition back to the subphase with monolayer compression. We find that the hydrophobic area, charge, and dipole all show correlations with both the mole fraction of antibiotic retained in the monolayer at the monolayer-bilayer equivalence pressure and the efficacies of these antibiotics against G-bacteria. Third, amine-rich gentamicin and the cationic antimicrobial peptides polymyxin B and colistin show no hydrophobic insertion but are instead strongly driven into the polar LPS layer by electrostatic interactions in a pressure-independent manner. Their intercalation stably increases the area per molecule (by up to 20%), which indicates massive formation of defects in the LPS layer. These defects support a self-promoted permeation mechanism of these antibiotics through the OM, which explains the high efficacy and specificity of these antimicrobials against G-bacteria.

Umbrella sampling, coupled with a weighted histogram analysis method (US-WHAM), can be used to construct potentials of mean force (PMFs) for studying the complex ion permeation pathways of membrane transport proteins. Despite the widespread use of US-WHAM, obtaining a physically meaningful PMF can be challenging. Here, we provide a protocol to resolve that issue. Then, we apply that protocol to compute a meaningful PMF for sodium ion permeation through channelrhodopsin chimera, C1C2, for illustration.

The interplay of a rapidly changing climate and infectious disease occurrence is emerging as a critical topic, requiring investigation of possible direct, as well as indirect, connections between disease processes and climate-related variation and phenomena. First, we introduce and overview three infectious disease exemplars (dengue, influenza, valley fever) representing different transmission classes (insect-vectored, human-to-human, environmentally-transmitted) to illuminate the complex and significant interplay between climate disease processes, as well as to motivate discussion of how Sandia can transform the field, and change our understanding of climate-driven infectious disease spread. We also review state-of-the-art epidemiological and climate modeling approaches, together with data analytics and machine learning methods, potentially relevant to climate and infectious disease studies. We synthesize the modeling and disease exemplars information, suggesting initial avenues for research and development (R&D) in this area, and propose potential sponsors for this work. Whether directly or indirectly, it is certain that a rapidly changing climate will alter global disease burden. The trajectory of climate change is an important control on this burden, from local, to regional and global scales. The efforts proposed herein respond to the National Research Councils call for the creation of a multidisciplinary institute that would address critical aspects of these interlocking, cascading crises.

Abstract not provided.

Two bacterial type II l-asparaginases, from Escherichia coli and Dickeya chrysanthemi, have played a critical role for more than 40 years as therapeutic agents against juvenile leukemias and lymphomas. Despite a long history of successful pharmacological applications and the apparent simplicity of the catalytic reaction, controversies still exist regarding major steps of the mechanism. In this report, we provide a detailed description of the reaction catalyzed by E. coli type II l-asparaginase (EcAII). Our model was developed on the basis of new structural and biochemical experiments combined with previously published data. The proposed mechanism is supported by quantum chemistry calculations based on density functional theory. We provide strong evidence that EcAII catalyzes the reaction according to the double-displacement (ping-pong) mechanism, with formation of a covalent intermediate. Several steps of catalysis by EcAII are unique when compared to reactions catalyzed by other known hydrolytic enzymes. Here, the reaction is initiated by a weak nucleophile, threonine, without direct assistance of a general base, although a distant general base is identified. Furthermore, tetrahedral intermediates formed during the catalytic process are stabilized by a never previously described motif. Although the scheme of the catalytic mechanism was developed only on the basis of data obtained from EcAII and its variants, this novel mechanism of enzymatic hydrolysis could potentially apply to most (and possibly all) l-asparaginases.

Ions transiting biomembranes might pass readily from water through ion-specific membrane proteins if these protein channels provide environments similar to the aqueous solution hydration environment. Indeed, bulk aqueous solution is an important reference condition for the ion permeation process. Assessment of this hydration mimicry concept depends on understanding the hydration structure and free energies of metal ions in water in order to provide a comparison for the membrane channel environment. To refine these considerations, we review local hydration structures of ions in bulk water and the molecular quasi-chemical theory that provides hydration free energies. In doing so, we note some current views of ion binding to membrane channels and suggest new physical chemical calculations and experiments that might further clarify the hydration mimicry concept.

Mixed solvents (i.e., binary or higher order mixtures of ionic or nonionic liquids) play crucial roles in chemical syntheses, separations, and electrochemical devices because they can be tuned for specific reactions and applications. Apart from fully explicit solvation treatments that can be difficult to parameterize or computationally expensive, there is currently no well-established first-principles regimen for reliably modeling atomic-scale chemistry in mixed solvent environments. We offer our perspective on how this process could be achieved in the near future as mixed solvent systems become more explored using theoretical and computational chemistry. We first outline what makes mixed solvent systems far more complex compared to single-component solvents. An overview of current and promising techniques for modeling mixed solvent environments is provided. We focus on so-called hybrid solvation treatments such as the conductor-like screening model for real solvents and the reference interaction site model, which are far less computationally demanding than explicit simulations. We also propose that cluster-continuum approaches rooted in physically rigorous quasi-chemical theory provide a robust, yet practical, route for studying chemical processes in mixed solvents.

Abstract not provided.

Molecular-level understanding and characterization of solvation environments are often needed across chemistry, biology, and engineering. Toward practical modeling of local solvation effects of any solute in any solvent, we report a static and all-quantum mechanics-based cluster-continuum approach for calculating single-ion solvation free energies. This approach uses a global optimization procedure to identify low-energy molecular clusters with different numbers of explicit solvent molecules and then employs the smooth overlap for atomic positions learning kernel to quantify the similarity between different low-energy solute environments. From these data, we use sketch maps, a nonlinear dimensionality reduction algorithm, to obtain a two-dimensional visual representation of the similarity between solute environments in differently sized microsolvated clusters. After testing this approach on different ions having charges 2+, 1+, 1-, and 2-, we find that the solvation environment around each ion can be seen to usually become more similar in hand with its calculated single-ion solvation free energy. Without needing either dynamics simulations or an a priori knowledge of local solvation structure of the ions, this approach can be used to calculate solvation free energies within 5% of experimental measurements for most cases, and it should be transferable for the study of other systems where dynamics simulations are not easily carried out.

Abstract not provided.