OPLS-AA force field parameters have been developed and validated for use in the simulation of 68 unique combinations of room temperature ionic liquids featuring 1-alkyl-3-methylimidazolium [RMIM] (R = Me, Et, Bu, Hex, Oct), N-alkylpyridinium [RPyr], and choline cations, along with Cl(-), PF6(-), BF4(-), NO3(-), AlCl4(-), Al2Cl7(-), TfO(-), saccharinate, and acesulfamate anions. The new parameters were fit to conformational profiles from gas-phase ab initio calculations at the LMP2/cc-pVTZ(-f)//HF/6-31G(d) theory level and compared to experimental condensed-phase structural and thermodynamic data. Monte Carlo simulations of the ionic liquids gave relative deviations from experimental densities of ca. 1-3% at 25 °C for most combinations and also yielded close agreement over a temperature range of 5 to 90 °C. Predicted heats of vaporization compared well with available experimental data and estimates. Transferability of the new parameters to multiple alkyl side-chain lengths for [RMIM] and [RPyr] was determined to give excellent agreement with charges and torsion potentials developed specific to desired alkyl lengths in 35 separate ionic liquid simulations. As further validation of the newly developed parameters, the Kemp elimination reaction of benzisoxazole via piperidine was computed in 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6] using mixed quantum and molecular mechanics (QM/MM) simulations and was found to give close agreement with the experimental free energy of activation.

Our OPLS-2009IL force field parameters (J. Chem. Theory Comput. 2009, 5, 1038-1050) were originally developed and tested on 68 unique ionic liquids featuring the 1-alkyl-3-methylimidazolium [RMIM], N-alkylpyridinium [RPyr], and choline cations. Experimental validation was limited to densities and a few, largely conflicting, heat of vaporization (ΔH) values reported in the literature at the time. Owing to the use of Monte Carlo as our sampling technique, it was also not possible to investigate the reproduction of dynamics. The [RMIM] OPLS-2009IL parameters have been revisited in this work and adapted for use in molecular dynamics (MD) simulations. In addition, new OPLS-AA parameters have been developed for multiple anions, i.e., AlCl, BF, Br, Cl, NO, PF, acetate, benzoate bis(pentafluoroethylsulfonyl)amide, bis(trifluoroethylsulfonyl)amide, dicyanamide, formate, methylsulfate, perchlorate, propanoate, thiocyanate, tricyanomethanide, and trifluoromethanesulfonate. The computed solvent densities, heats of vaporization, viscosities, diffusion coefficients, heat capacities, surface tensions, and other relevant solvent data compared favorably with experiment. A charge scaling of ±0.8 e was also investigated as a means to mimic polarization and charge transfer effects. The 0.8-scaling led to significant improvements for ΔH, surface tension, and self-diffusivity; however, a concern when scaling charges is the potential degradation of local intermolecular interactions at short ranges. Radial distribution functions (RDFs) were used to examine cation-anion interactions when employing 0.8*OPLS-2009IL and the scaled force field accurately reproduced RDFs from ab initio MD simulations.

Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.

Deep eutectic solvents (DES) are a class of solvents frequently composed of choline chloride and a neutral hydrogen bond donor (HBD) at ratios of 1:1, 1:2, or 1:3, respectively. As cost-effective and eco-friendly solvents, DESs have gained considerable popularity in multiple fields, including materials, separations, and nanotechnology. In the present work, a comprehensive set of transferable parameters have been fine-tuned to accurately reproduce bulk-phase physical properties and local intermolecular interactions for 8 different choline chloride-based DESs. This nonpolarizable force field, OPLS-DES, gave near quantitative agreement at multiple temperatures for experimental densities, viscosities, heat capacities, and surface tensions yielding overall mean absolute errors (MAEs) of ca. 1.1%, 1.6%, 5.5%, and 1.5%, respectively. Local interactions and solvent structuring between the ions and HBDs, including urea, glycerol, phenol, ethylene glycol, levulinic acid, oxalic acid, and malonic acid, were accurately reproduced when compared to radial distribution functions and coordination numbers derived from experimental liquid-phase neutron diffraction data and from first-principles molecular dynamics simulations. The reproduction of transport properties presented a considerable challenge and behaved more like a supercooled liquid near room temperature; higher-temperature simulations, e.g., 400-500 K, or an alternative polarizable force field is recommended when computing self-diffusion coefficients.

CONSPECTUS-Application of combined quantum and molecular mechanical (QM/MM) methods focuses on predicting activation barriers and the structures of stationary points for organic and enzymatic reactions. Characterization of the factors that stabilize transition structures in solution and in enzyme active sites provides a basis for design and optimization of catalysts. Continued technological advances allowed expansion from prototypical cases to mechanistic studies featuring detailed enzyme and condensed-phase environments with full integration of the QM calculations and configurational sampling. This required improved algorithms featuring fast QM methods, advances in computing changes in free energies including free-energy perturbation (FEP) calculations, and enhanced configurational sampling. In particular, the present Account highlights development of the PDDG/PM3 semiempirical QM method, computation of multidimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo (MC) simulations, and a polynomial quadrature method for efficient modeling of proton-transfer reactions.The utility of this QM/MM/MC/FEP methodology is illustrated for a variety of organic reactions including substitution, decarboxylation, elimination, and pericyclic reactions. Comparison with experimental kinetic results on medium effects has verified the accuracy of the QM/MM approach in the full range of solvents from hydrocarbons to water to ionic liquids. Corresponding results from NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ab initio and density functional theory (DFT) methods with continuum-based treatments of solvation reveal deficiencies, particularly for protic solvents. Also summarized in this Account are three specific QM/MM applications to biomolecular systems: (1) a recent study that clarified the mechanism for the reaction of 2-pyrone derivatives catalyzed by macrophomate synthase as a tandem Michael-aldol sequence rather than a Diels-Alder reaction; (2) elucidation of the mechanism of action of fatty acid amide hydrolase (FAAH), an unusual Ser-Ser-Lys proteolytic enzyme; and, (3) the construction of enzymes for Kemp elimination of 5-nitrobenzisoxazole that highlights the utility of QM/MM in the design of artificial enzymes.