NMR study of heterogeneity in pyridine-N-oxide...HCl crystal

An origin of narrow ¹H NMR signals in pyridine-N-oxide (PyO)...HCl crystal has been investigated by means of MAS, SPEDAS, NOESY and COSY techniques. Spectra of crystalline samples are compared with those of solid phase obtained from liquid PyO...HCl solutions (in acetonitile/H₂O) after the heterogeneous phase separation. It has been concluded that partially resolved peaks in ¹H NMR spectra of solids are related with heterogeneity of spin system and presence of different H-bond clusters of water molecules. NOESY spectra show no cross-peaks even at very long mixing time (500 ms). This indicates there is no exchange process between spins causing different peaks, and thus the corresponding molecular aggregates are captured in “islands of mobility8 without any channels sufficient for exchange. Appearance of MAS side bands as “pseudo8 cross-peaks in 2D NMR spectra using MAS/COSY technique is reported. In the case of accidental coincidence of spinning frequency (ω _MAS ) with spectral distances between some diagonal signals, intensive non-diagonal peaks are observed at the corresponding cross-positions. A misleading conclusion concerning spin coupling is easy to avoid using various ω _MAS . This work is dedicated to Professor Robert Blinc on the occasion of his 70^th birthday.     

Large scale relative protein ligand binding affinities using non-equilibrium alchemy

Ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design. However, their broad uptake and impact is held back by the notoriously complex setup of the calculations. Only a few tools other than the free energy perturbation approach by Schrödinger Inc. (referred to as FEP+) currently enable end-to-end application. Here, we present for the first time an approach based on the open-source software pmx that allows to easily set up and run alchemical calculations for diverse sets of small molecules using the GROMACS MD engine. The method relies on theoretically rigorous non-equilibrium thermodynamic integration (TI) foundations, and its flexibility allows calculations with multiple force fields. In this study, results from the Amber and Charmm force fields were combined to yield a consensus outcome performing on par with the commercial FEP+ approach. A large dataset of 482 perturbations from 13 different protein–ligand datasets led to an average unsigned error (AUE) of 3.64 ± 0.14 kJ mol⁻¹, equivalent to Schrödinger''s FEP+ AUE of 3.66 ± 0.14 kJ mol⁻¹. For the first time, a setup is presented for overall high precision and high accuracy relative protein–ligand alchemical free energy calculations based on open-source software.

Relative ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design.     

Thermodynamic properties underlying the alpha-helix-to-beta-sheet transition, aggregation, and amyloidogenesis of polylysine as probed by calorimetry, densimetry, and ultrasound velocimetry

In this work, we performed a detailed thermodynamic study of an aggregation-prone polypeptide, polylysine, to gain a deeper insight into the scenario of physicochemical events during its unfolding, aggregation, and amyloidogenesis. The precise and simultaneous determination of the partial molar volume, the heat capacity, and the coefficients of thermal expansion, as well as adiabatic and isothermal compressibility of the protein upon unfolding and aggregation, yields a thermodynamic picture of the aggregation process highlighting the importance of volume fluctuations during unfolding and amyloidogenesis of proteins.     

Stochastic Dynamic Aircraft System Conflict Distribution under Uncertainties

A dynamic aircraft system conflict (concurrent event) situation exists when a time with a loss (-es) of separation (LOS) in their true or predicted trajectories is determined. Regional air traffic management (ATM) programs aim to make ATM safer and more efficient through a higher level of automation for such processes as dynamic aircraft systems concurrent events detection and, consequently, resolution. Therefore, wind and aircraft speed uncertainty parameters should be properly addressed. This paper offers an approach to a dynamic aircraft system flying under a certain concurrent event situation and demonstrates situation stochastic distribution results (output) based on determined wind speed values (while wind direction angles and the dynamic aircraft system speed values are random). Based on these facts, the stochastic dynamic aircraft system conflict distribution information under determined and random parameters might be retrieved at any specific (preferred) time moment. The observations of this study disclosed that such stochastic output data might have a certain impact on safety matters (potential “domino effect” conflicts on a horizontal plane) and on the efficiency (i.e., flight distance which eventually is a determinant of flight time, fuel costs, delays, emissions, monitoring, etc.).     

Hydrazones Possessing a Phenyl-1,2,3,4-tetrahydroquinoline Moiety as Hole Transporting Materials

Summary.  Hydrazones containing 1-phenyl-1,2,3,4-tetrahydroquinoline units were synthesized starting from diphenylamine. These compounds were found to constitute novel hole transporting materials and were characterized by the time of flight method. The hole drift mobility in these compounds exceeds 10⁻⁶ cm² V⁻¹ s⁻¹ at an electric field of 10⁶ V cm⁻¹.     

Limits of the Letac principle. The discrete case

The Letac principle says that if the backward iterations of a random function converge almost surely, then the forward iterations converge in distribution. In this paper, we find conditions for the inverse implication to hold.     

Development of a Gas-Tight Syringe Headspace GC-FID Method for the Detection of Ethanol,and a Description of the Legal and Practical Framework for Its Analysis,in Samples of English and Welsh Motorists’ Blood and Urine

Ethanol is the most commonly used recreational drug worldwide. This study describes the development and validation of a headspace gas chromatography flame ionisation detection (HS-GC-FID) method using dual columns and detectors for simultaneous separation and quantitation. The use of a dual-column, dual-detector HS-GC-FID to quantitate ethanol is a common analytical technique in forensic toxicology; however, most analytical systems utilise pressure-balance injection rather than a simplified gas-tight syringe, as per this technique. This study is the first to develop and validate a technique that meets the specifications of the United Kingdom’s requirements for road traffic toxicology testing using a Shimadzu GC-2014 gas-tight syringe. The calibration ranged from 10 to 400 mg/100 mL, with a target minimum linearity of r2 > 0.999, using tertiary butanol as the internal standard marker. The method has an expanded uncertainty at 99.73% confidence of 3.64% at 80 mg/100 mL, which is the blood alcohol limit for drink driving in England and Wales. In addition, at 200 mg%—the limit at which a custodial sentence may be imposed on the defendant—the expanded uncertainty was 1.95%. For both the 80 mg% and 200 mg% concentrations, no bias was present in the analytical method. This method displays sufficient separation for other alcohols, such as methanol, isopropanol, acetaldehyde, and acetone. The validation of this technique complies with the recommended laboratory guidelines set out by United Kingdom and Ireland Association of Forensic Toxicologists (UKIAFT), the recently issued Laboratory 51 guidelines by the United Kingdom Accreditation Service (UKAS), and the criteria set out by the California Code of Regulations (CCR), 17 CCR § 1220.1.