Mechanism of Catalysis by l-Asparaginase.

Two bacterial type II l-asparaginases, from and , 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 type II l-asparaginase (EcAII).

Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia.

We and others have reported that the anticancer activity of L-asparaginase (ASNase) against asparagine synthetase (ASNS)-positive cell types requires ASNase glutaminase activity, whereas anticancer activity against ASNS-negative cell types does not. Here, we attempted to disentangle the relationship between asparagine metabolism, glutamine metabolism, and downstream pathways that modulate cell viability by testing the hypothesis that ASNase anticancer activity is based on asparagine depletion rather than glutamine depletion per se. We tested ASNase wild-type (ASNase) and its glutaminase-deficient Q59L mutant (ASNase) and found that ASNase glutaminase activity contributed to durable anticancer activity against xenografts of the ASNS-negative Sup-B15 leukemia cell line in NOD/SCID gamma mice, whereas asparaginase activity alone yielded a mere growth delay.

Quasi-Chemical Theory with Cluster Sampling from Ab Initio Molecular Dynamics: Fluoride (F) Anion Hydration.

Accurate predictions of the hydration free energy for anions typically has been more challenging than that for cations. Hydrogen bond donation to the anion in hydrated clusters such as F(HO) can lead to delicate structures. Consequently, the energy landscape contains many local minima, even for small clusters, and these minima present a challenge for computational optimization.

Probing key elements of teixobactin-lipid II interactions in membranes.

Teixobactin (Txb) is a recently discovered antibiotic against Gram-positive bacteria that induces no detectable resistance. The bactericidal mechanism is believed to be the inhibition of cell wall biosynthesis by Txb binding to lipid II and lipid III. Txb binding specificity likely arises from targeting of the shared lipid component, the pyrophosphate moiety.

Molecular Dynamics of Lithium Ion Transport in a Model Solid Electrolyte Interphase.

Li transport within a solid electrolyte interphase (SEI) in lithium ion batteries has challenged molecular dynamics (MD) studies due to limited compositional control of that layer. In recent years, experiments and ab initio simulations have identified dilithium ethylene dicarbonate (LiEDC) as the dominant component of SEI layers. Here, we adopt a parameterized, non-polarizable MD force field for LiEDC to study transport characteristics of Li in this model SEI layer at moderate temperatures over long times.

Strontium and barium in aqueous solution and a potassium channel binding site.

Ion hydration structure and free energy establish criteria for understanding selective ion binding in potassium (K) ion channels and may be significant to understanding blocking mechanisms as well. Recently, we investigated the hydration properties of Ba, the most potent blocker of K channels among the simple metal ions. Here, we use a similar method of combining ab initio molecular dynamics simulations, statistical mechanical theory, and electronic structure calculations to probe the fundamental hydration properties of Sr, which does not block bacterial K channels.

Comparison of single-ion molecular dynamics in common solvents.

Laying a basis for molecularly specific theory for the mobilities of ions in solutions of practical interest, we report a broad survey of velocity autocorrelation functions (VACFs) of Li and PF ions in water, ethylene carbonate, propylene carbonate, and acetonitrile solutions. We extract the memory function, γ(t), which characterizes the random forces governing the mobilities of ions. We provide comparisons controlling for the effects of electrolyte concentration and ion-pairing, van der Waals attractive interactions, and solvent molecular characteristics.

Role of Solute Attractive Forces in the Atomic-Scale Theory of Hydrophobic Effects.

The role that van der Waals (vdW) attractive forces play in the hydration and association of atomic hydrophobic solutes such as argon (Ar) in water is reanalyzed using the local molecular field (LMF) theory of those interactions. In this problem, solute vdW attractive forces can reduce or mask hydrophobic interactions as measured by contact peak heights of the ArAr correlation function compared to reference results for purely repulsive core solutes. Nevertheless, both systems exhibit a characteristic hydrophobic inverse temperature behavior in which hydrophobic association becomes stronger with increasing temperature through a moderate temperature range.

Molecular Simulation Results on Charged Carbon Nanotube Forest-Based Supercapacitors.

Electrochemical double-layer capacitances of charged carbon nanotube (CNT) forests with tetraethyl ammonium tetrafluoro borate electrolyte in propylene carbonate are studied on the basis of molecular dynamics simulation. Direct molecular simulation of the filling of pore spaces of the forest is feasible even with realistic, small CNT spacings. The numerical solution of the Poisson equation based on the extracted average charge densities then yields a regular experimental dependence on the width of the pore spaces, in contrast to the anomalous pattern observed in experiments on other carbon materials and also in simulations on planar slot-like pores.

Nanoporous Hydrogels for the Observation of Anthrax Exotoxin Translocation Dynamics.

The ability to observe lethal anthrax exotoxins translocating through size-constricting nanopores in vitro, combined with detailed sequence and structural data, has aided in elucidated mechanisms of exotoxin cell entry and toxicity. However, due to limited observations of anthrax exotoxins translocating through protective antigen nanopores in vitro and the instability of protective antigen-functionalized suspended lipid bilayers, questions remain regarding the native mechanisms of cell entry. Nanoporous hydrogel membranes offer a robust tool for studying protein translocation with ensemble measurements that complement conventional single-molecule translocation measurements.

Assessment of Simple Models for Molecular Simulation of Ethylene Carbonate and Propylene Carbonate as Solvents for Electrolyte Solutions.

Progress in understanding liquid ethylene carbonate (EC) and propylene carbonate (PC) on the basis of molecular simulation, emphasizing simple models of interatomic forces, is reviewed. Results on the bulk liquids are examined from the perspective of anticipated applications to materials for electrical energy storage devices. Preliminary results on electrochemical double-layer capacitors based on carbon nanotube forests and on model solid-electrolyte interphase (SEI) layers of lithium ion batteries are considered as examples.

Molecular-Scale Description of SPAN80 Desorption from a Squalane-Water Interface.

Extensive all-atom molecular dynamics calculations on the water-squalane interface for nine different loadings with sorbitan monooleate (SPAN80), at T = 300 K, are analyzed for the surface tension equation of state, desorption free-energy profiles as they depend on loading, and to evaluate escape times for adsorbed SPAN80 into the bulk phases. These results suggest that loading only weakly affects accommodation of a SPAN80 molecule by this squalane-water interface. Specifically, the surface tension equation of state is simple through the range of high tension to high loading studied, and the desorption free-energy profiles are weakly dependent on loading here.

Quasi-chemical theory of F(aq): The "no split occupancies rule" revisited.

We use ab initio molecular dynamics (AIMD) calculations and quasi-chemical theory (QCT) to study the inner-shell structure of F(aq) and to evaluate that single-ion free energy under standard conditions. Following the "no split occupancies" rule, QCT calculations yield a free energy value of -101 kcal/mol under these conditions, in encouraging agreement with tabulated values (-111 kcal/mol). The AIMD calculations served only to guide the definition of an effective inner-shell constraint.

Scaling Atomic Partial Charges of Carbonate Solvents for Lithium Ion Solvation and Diffusion.

Lithium-ion solvation and diffusion properties in ethylene carbonate (EC) and propylene carbonate (PC) were studied by molecular simulation, experiments, and electronic structure calculations. Studies carried out in water provide a reference for interpretation. Classical molecular dynamics simulation results are compared to ab initio molecular dynamics to assess nonpolarizable force field parameters for solvation structure of the carbonate solvents.

Statistical Analyses of Hydrophobic Interactions: A Mini-Review.

This review focuses on the striking recent progress in solving for hydrophobic interactions between small inert molecules. We discuss several new understandings. First, the inverse temperature phenomenology of hydrophobic interactions, i.

Dielectric Relaxation of Ethylene Carbonate and Propylene Carbonate from Molecular Dynamics Simulations.

Ethylene carbonate (EC) and propylene carbonate (PC) are widely used solvents in lithium (Li)-ion batteries and supercapacitors. Ion dissolution and diffusion in those media are correlated with solvent dielectric responses. Here, we use all-atom molecular dynamics simulations of the pure solvents to calculate dielectric constants and relaxation times, and molecular mobilities.

Dispersion- and Exchange-Corrected Density Functional Theory for Sodium Ion Hydration.

A challenge in density functional theory is developing functionals that simultaneously describe intermolecular electron correlation and electron delocalization. Recent exchange-correlation functionals address those two issues by adding corrections important at long ranges: an atom-centered pairwise dispersion term to account for correlation and a modified long-range component of the electron exchange term to correct for delocalization. Here we investigate how those corrections influence the accuracy of binding free energy predictions for sodium-water clusters.

Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase.

Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer treatment for over four decades, yet their exact reaction mechanism remains elusive. L-ASP from Escherichia coli deamidates asparagine (Asn) and glutamine, with an ~10(4) higher specificity (kcat/Km) for asparagine despite only one methylene difference in length. Through a sensitive kinetic approach, we quantify competition among the substrates and interpret its clinical role.

Octa-Coordination and the Aqueous Ba(2+) Ion.

The hydration structure of Ba(2+) ion is important for understanding blocking mechanisms in potassium ion channels. Here, we combine statistical mechanical theory, ab initio molecular dynamics simulations, and electronic structure methods to calculate the hydration free energy and local hydration structure of Ba(2+)(aq). The predicted hydration free energy (-304 ± 1 kcal/mol) agrees with the experimental value (-303 kcal/mol) when a maximally occupied, unimodal inner solvation shell is treated.