Thermal Activation of Methane by MgO+: Temperature Dependent Kinetics, Reactive Molecular Dynamics Simulations and Statistical Modeling

The kinetics of MgO + + CH 4 was studied experimentally using the variable ion source, temperature adjustable selected ion flow tube (VISTA-SIFT) apparatus from 300 − 600 K and computationally by running and analyzing reactive atomistic simula- tions. Rate coefficients and product branching fractions were determined as a function of temperature. The reaction proceeded with a rate of k = 5 . 9 ± 1 . 5 × 10 − 10 ( T/ 300 K) − 0 . 5 ± 0 . 2 cm 3 s − 1 . MgOH + was the dominant product at all temperatures, but Mg + , the co-product of oxygen-atom transfer to form methanol, was observed with a product branching fraction of 0 . 08 ± 0 . 03( T/ 300 K) − 0 . 8 ± 0 . 7 . Reactive molecular dynamics simulations using a reactive force field, as well as a neural network trained on thousands of structures yield rate coefficients about one order of magnitude lower. This underestimation of the rates is traced back to the multireference character of the transition state [MgOCH 4 ] + . Statistical modeling of the temperature-dependent kinetics provides further insight into the reactive potential surface. The rate limiting step was found to be consistent with a four-centered activation of the C-H bond, consistent with previous calculations. The product branching was modeled as a competition between dissociation of an insertion intermediate directly after the rate- limiting transition state, and traversing a transition state corresponding to a methyl migration leading to a Mg-CH 3 OH + complex, though only if this transition state is stabilized significantly relative to the dissociated MgOH + + CH 3 product channel. An alternative non-statistical mechanism is discussed, whereby a post-transition state bifurcation in the potential surface could allow the reaction to proceed directly from the four-centered TS to the Mg-CH 3 OH + complex thereby allowing a more robust competition between the product channels

Investigation of the impact of urine handling procedures on interpretation of urinalysis findings and product safety in subjects treated with ezogabine

Neil Brickel,1 Sarah DeRossett,2 Mauro Buraglio,3 Christopher Evans,4 Si&ocirc;n Jones51Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, Middlesex, UK; 2Neurosciences Therapy Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Neurosciences Therapy Area Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 4Bioanalytical Science and Toxicokinetics, PTS-DMPK, GlaxoSmithKline, King of Prussia, PA, USA; 5Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, Middlesex, UKBackground: Ezogabine (also known by the international nonproprietary name of retigabine) is an antiepileptic drug codeveloped and comarketed by Valeant Pharmaceuticals North America and GlaxoSmithKline, which reduces neuronal excitability by enhancing the activity of potassium channels and has the potential to have effects on the urinary system through a pharmacologic action on bladder smooth muscle. In a single post-herpetic neuralgia trial, but not in an extensive epilepsy development program, proteinuria was unexpectedly reported in patients receiving ezogabine. Consequently, investigations were conducted to determine whether the reported proteinuria represented a true or false-positive finding.Methods: Patients receiving ezogabine 900&ndash;1200 mg/day in an open-label extension (Study 303) of a Phase III epilepsy trial voluntarily provided urine samples. Fresh samples were analyzed immediately at the study site, and stabilized aliquots were analyzed 1&ndash;3 days after collection at two central laboratories. In an open-label study in healthy volunteers receiving ezogabine 600&ndash;900 mg/day (Study RTG114137), urine samples were analyzed fresh (<2 hours after collection) and, using two different stabilizers and storage at room temperature, after 24 and 72 hours. Fluid intake was restricted prior to one sample point. Albumin:creatinine ratios were assessed in both studies.Results: In Study 303, there was notable variation in clarity, color, and proteinuria between fresh and stored urine samples, and between samples analyzed at different laboratories. In RTG114137, reporting rates of proteinuria were elevated following storage using one stabilizer, and the frequency of color change from fresh to stored samples differed between the stabilizers and between 24 and 72 hours with one stabilizer. Following fluid restriction, proteinuria rates were elevated with both stabilizers. Poor tolerability of ezogabine 750&ndash;900 mg/day resulted in limited titration beyond 750 mg/day and early termination of RTG114137.Conclusion: Hydration status, interval between urine collection and analysis, and the type of stabilizer used are all factors that may lead to false-positive proteinuria findings in patients receiving ezogabine and should be borne in mind if abnormalities are reported.Keywords: antiepileptic drugs, ezogabine, retigabine, urinary safety, urinalysi

Q-RepEx : A Python pipeline to increase the sampling of empirical valence bond simulations

The exploration of chemical systems occurs on complex energy landscapes. Comprehensively sampling rugged energy landscapes with many local minima is a common problem for molecular dynamics simulations. These multiple local minima trap the dynamic system, preventing efficient sampling. This is a particular challenge for large biochemical systems with many degrees of freedom. Replica exchange molecular dynamics (REMD) is an approach that accelerates the exploration of the conformational space of a system, and thus can be used to enhance the sampling of complex biomolecular processes. In parallel, the empirical valence bond (EVB) approach is a powerful approach for modeling chemical reactivity in biomolecular systems. Here, we present an open-source Python-based tool that interfaces with the Q simulation package, and increases the sampling efficiency of the EVB free energy perturbation/umbrella sampling approach by means of REMD. This approach, Q-RepEx, both decreases the computational cost of the associated REMD-EVB simulations, and opens the door to more efficient studies of biochemical reactivity in systems with significant conformational fluctuations along the chemical reaction coordinate

La vie de Marianne, ou Les avantures de Mme la comtesse de ***. 1e partie / , par M. de Marivaux. Première partie

[La vie de Marianne (français)