Mechanisms of acetylcholinesterase protection against sarin and soman by adenosine A1 receptor agonist N6-cyclopentyladenosine.

Organophosphorus nerve agents (NAs) irreversibly inhibit acetylcholinesterase (AChE), the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh). The over accumulation of ACh after NA exposure leads to cholinergic toxicity, seizure, and death. Current medical countermeasures effectively mitigate peripheral symptoms, however; the brain is often unprotected. Alternative acute treatment with the adenosine A1 receptor agonist N6-cyclopentyladensosine (CPA) has previously been demonstrated to prevent AChE inhibition as well as to suppress neuronal activity. The mechanism of AChE protection is unknown. To elucidate the feasibility of potential CPA-AChE interaction mechanisms, we applied a truncated molecular model approach and density functional theory. The candidate mechanisms studied are reversible enzyme inhibition, enzyme reactivation, and NA blocking prior to enzyme conjugation. Our thermodynamic data suggest that CPA can compete with the NAs sarin and soman for the active site of AChE, but may, in contrast to NAs, undergo back-reaction. We found a strong interaction between CPA and NA conjugated AChE, making enzyme reactivation unlikely but possibly allowing for CPA protection through the prevention of NA aging. The data also indicates that there is an affinity between CPA and unbound NAs. The results from this study support the hypothesis that CPA counters NA toxicity via multiple mechanisms and is a promising therapeutic strategy that warrants further development.

Van der Waals interfaces in epitaxial vertical metal/2D/3D semiconductor heterojunctions of monolayer MoS2 and GaN.

A promising approach for high speed and high power electronics is to integrate two-dimensional (2D) materials with conventional electronic components such as bulk (3D) semiconductors and metals. In this study we explore a basic integration step of inserting a single monolayer MoS2 (1L-MoS2) inside a Au/p-GaN junction and elucidate how it impacts the structural and electrical properties of the junction. Epitaxial 1L-MoS2 in the form of 1-2 µm triangle domains are grown by powder vaporization on a p-doped GaN substrate, and the Au capping layer is deposited by evaporation. Transmission electron microscopy (TEM) of the van der Waals interface indicates that 1L-MoS2 remained distinct and intact between the Au and GaN and that the Au is epitaxial to GaN only when the 1L-MoS2 is present. Quantitative TEM analyses of the van der Waals interfaces are performed and yielded the atomic plane spacings in the heterojunction. Electrical characterization of the all-epitaxial, vertical Au/1L-MoS2/p-GaN heterojunctions enables the derivations of Schottky barrier heights (SBH) and drawing of the band alignment diagram. Notably, 1L-MoS2 appears to be electronically semi-transparent, and thus can be considered as a modifier to the Au contact rather than an independent semiconductor component forming a pn-junction. The I-V analysis and our first principles calculation indicated Fermi level pinning and substantial band bending in GaN at the interface. Lastly, we illustrate how the depletion regions are formed in a bipolar junction with an ultrathin monolayer component using the calculated distribution of the charge density across the Au/1L-MoS2/GaN junction.

Blind test of density-functional-based methods on intermolecular interaction energies.

In the past decade, a number of approaches have been developed to fix the failure of (semi)local density-functional theory (DFT) in describing intermolecular interactions. The performance of several such approaches with respect to highly accurate benchmarks is compared here on a set of separation-dependent interaction energies for ten dimers. Since the benchmarks were unknown before the DFT-based results were collected, this comparison constitutes a blind test of these methods.

A coarse-grain force field for RDX: Density dependent and energy conserving.

We describe the development of a density-dependent transferable coarse-grain model of crystalline hexahydro-1,3,5-trinitro-s-triazine (RDX) that can be used with the energy conserving dissipative particle dynamics method. The model is an extension of a recently reported one-site model of RDX that was developed by using a force-matching method. The density-dependent forces in that original model are provided through an interpolation scheme that poorly conserves energy. The development of the new model presented in this work first involved a multi-objective procedure to improve the structural and thermodynamic properties of the previous model, followed by the inclusion of the density dependency via a conservative form of the force field that conserves energy. The new model accurately predicts the density, structure, pressure-volume isotherm, bulk modulus, and elastic constants of the RDX crystal at ambient pressure and exhibits transferability to a liquid phase at melt conditions.

Intermolecular forces and molecular dynamics simulation of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) using symmetry adapted perturbation theory.

The dimer potential energy surface (PES) of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) has been explored using symmetry adapted perturbation theory based on a Kohn-Sham density functional theory description of the monomers [SAPT(DFT)]. An intermolecular potential energy function was parametrized using a grid of 880 ab initio SAPT(DFT) dimer interaction energies, and the function was used to identify stationary points on the SAPT(DFT) dimer PES. It is shown that there exists a variety of minima with a range of bonding configurations and ab initio analyses of the interaction energy components, along with radial cross sections of the PES near each minimum, are presented. Results of isothermal-isostress molecular dynamics simulations are reported, and the simulated structure, thermal expansion, sublimation enthalpy, and bulk modulus of the TATB crystal, based on the SAPT(DFT) interaction potential, are in good agreement with experiment.

The effects of stoichiometry on the mechanical properties of icosahedral boron carbide under loading.

The effects of stoichiometry on the atomic structure and the related mechanical properties of boron carbide (B(4)C) have been studied using density functional theory and quantum molecular dynamics simulations. Computational cells of boron carbide containing up to 960 atoms and spanning compositions ranging from 6.7% to 26.7% carbon were used to determine the effects of stoichiometry on the atomic structure, elastic properties, and stress-strain response as a function of hydrostatic, uniaxial, and shear loading paths. It was found that different stoichiometries, as well as variable atomic arrangements within a fixed stoichiometry, can have a significant impact on the yield stress of boron carbide when compressed uniaxially (by as much as 70% in some cases); the significantly reduced strength of boron carbide under shear loading is also demonstrated.

A molecular dynamics study of 1,1-diamino-2,2-dinitroethylene (FOX-7) crystal using a symmetry adapted perturbation theory-based intermolecular force field.

A dimer potential energy function for 1,1-diamino-2,2-dinitroethylene (FOX-7) has been developed using symmetry adapted perturbation theory based on a Kohn-Sham density functional theory description of the monomers [SAPT(DFT)]. Interaction energies of 1008 dimer configurations were computed in an augmented double zeta basis set and fitted to an atom-atom intermolecular potential energy function of Coulomb plus Buckingham exp-6 form. The potential was used in isothermal-isostress molecular dynamics simulations to study the structure and thermal/pressure response of FOX-7 crystal. The simulated structure is in very good agreement with experiment and the computed thermal/pressure response of the crystal shows significant anisotropy with respect to crystallographic direction, in-line with experimental observations. It is concluded that SAPT(DFT) is an excellent method for development of intermolecular potentials for energetic molecular crystals.

Theoretical methodology for prediction of tropospheric oxidation of dimethyl phosphonate and dimethyl methylphosphonate.

Rate constants for the reactions of OH radicals with dimethyl phosphonate [DMHP, (CH(3)O)(2)P(O)H] and dimethyl methylphosphonate [DMMP, (CH(3)O)(2)P(O)CH(3)] have been calculated by ab initio structural methods and semiclassical dynamics modeling and compared with experimental measurements over the temperature range 250-350 K. The structure and energetics of reactants and transition structures are determined for all hydrogen atom abstraction pathways that initiate the atmospheric oxidation mechanism. Structures are obtained at the CCSD/6-31++G** level of chemical theory, and the height of the activation barrier is determined by a variant of the G2MP2 method. A Transfer Hamiltonian is used to compute the minimum energy path in the neighborhood of the transition state (TS). This calculation provides information about the curvature of the potential energy surface in the neighborhood of the TS, as well as the internal forces that are needed by the semiclassical flux-flux autocorrelation function (SCFFAF) dynamics model used to compute the temperature-dependent reaction rate constants for the various possible abstraction pathways. The computed temperature-dependent rate curves frequently lie within the experimental error bars.

A pseudoatom approach to molecular truncation: application in ab initio MBPT methods.

In this paper, we test the performance of the molecular truncation method of Mallik et al., which was originally applied at the semiempirical NDDO level, in ab initio MBPT methods. Pseudoatoms developed for the replacement of -OCH(3) and -OCH(2)CH(3) functional groups are used in optimizations of selected clusters, and the resulting geometries are compared to reference values taken from the full molecules. It is shown that the pseudoatoms, which consist of parametrized effective core potentials for the nearest neighbor interactions and an external charge field for long-range Coulomb effects, perform well at the MP2 and CCSD levels of theory for the suite of molecules to which they were applied. Representative timings for some of the pseudoatom-terminated clusters are presented, and it is seen that there is a significant reduction in computational time, yet the geometric configurations and deprotonation energies of the pseudoatom-terminated clusters are comparable to the more computationally expensive all-atom molecules.