Virtual Screening with Gnina 1.0

Virtual screening—predicting which compounds within a specified compound library bind to a target molecule, typically a protein—is a fundamental task in the field of drug discovery. Doing virtual screening well provides tangible practical benefits, including reduced drug development costs, faster time to therapeutic viability, and fewer unforeseen side effects. As with most applied computational tasks, the algorithms currently used to perform virtual screening feature inherent tradeoffs between speed and accuracy. Furthermore, even theoretically rigorous, computationally intensive methods may fail to account for important effects relevant to whether a given compound will ultimately be usable as a drug. Here we investigate the virtual screening performance of the recently released Gnina molecular docking software, which uses deep convolutional networks to score protein-ligand structures. We find, on average, that Gnina outperforms conventional empirical scoring. The default scoring in Gnina outperforms the empirical AutoDock Vina scoring function on 89 of the 117 targets of the DUD-E and LIT-PCBA virtual screening benchmarks with a median 1% early enrichment factor that is more than twice that of Vina. However, we also find that issues of bias linger in these sets, even when not used directly to train models, and this bias obfuscates to what extent machine learning models are achieving their performance through a sophisticated interpretation of molecular interactions versus fitting to non-informative simplistic property distributions.     

Photonic crystal fibre as an optofluidic reactor for the measurement of photochemical kinetics with sub-picomole sensitivity

Photonic crystal fibre constitutes an optofluidic system in which light can be efficiently coupled into a solution-phase sample, contained within the hollow core of the fibre, over long path-lengths. This provides an ideal arrangement for the highly sensitive monitoring of photochemical reactions by absorption spectroscopy. We report here the use of UV/vis spectroscopy to measure the kinetics of the photochemical and thermal cis-trans isomerisation of sub-picomole samples of two azo dyes within the 19-μm diameter core of a photonic crystal fibre, over a path length of 30 cm. Photoisomerisation quantum yields are the first reported for "push-pull" azobenzenes in solution at room temperature; such measurements are challenging because of the fast thermal isomerisation process. Rate constants obtained for thermal isomerisation are in excellent agreement with those established previously in conventional cuvette-based measurements. The high sensitivity afforded by this intra-fibre method enables measurements in solvents in which the dyes are too insoluble to permit conventional cuvette-based measurements. The results presented demonstrate the potential of photonic crystal fibres as optofluidic elements in lab-on-a-chip devices for photochemical applications.     

Mass determination of megadalton-DNA electrospray ions using charge detection mass spectrometry

Charge detection mass spectrometry (CD-MS) has been used to determine the mass of double-stranded, circular DNA and single-stranded, circular DNA in the range of 2500 to 8000 base pairs (1.5–5.0 MDa). Simultaneous measurement of the charge and velocity of an electrostatically accelerated ion allows a mass determination of the ion, with instrument calibration determined independently of samples. Positive ion mass spectra of electrosprayed commercial DNA samples supplied in tris(hydroxymethyl)ethylenediaminetetraacetic acid buffer, diluted in 50 vol. % acetonitrile, were obtained without cleanup of the sample. A CD mass spectrum constructed from 3000 ion measurements takes 10 min to acquire and yields the DNA molecular mass directly (mass resolution = 6). The data collected represent progress toward a more automatable alternative to sizing of DNA by gel electrophoresis. In addition to the mass spectra, CD-MS generates charge versus mass plots, which provide another means to investigate the creation and fate of large electrospray ions.     

MAP: microwave-assisted extraction of cockroaches

A Microwave-Assisted Process (MAP is a Trade-Mark of Her Majesty the Queen in Right of Canada as represented by the Minister of the Environment) solvent extraction procedure was used in conjunction with GC-MS analysis to investigate the chemical composition of dried and live cockroaches. The main components extracted were classified into four groups: sterols. fatty acids and their esters, long chain alkanes and fused aromatic hydrocarbons.     

Efficient method to locate double bond positions in conjugated trienes

The double bond positions of 11 conjugated trienes were unambiguously located through a simple derivatization method amenable to nanogram-scale analyses. The trienes were reacted with the powerful dienophile 4-methyl-1,2,4-triazoline-3,5-dione (MTAD), and the mass spectra of the resulting cycloadducts exhibited large diagnostic fragments which allowed the unequivocal location of the double bonds in the parent triene in most cases. Catalytic hydrogenation of the cycloadducts produced saturated compounds with characteristic mass spectral fragments from which the positions of the trienes in the parent compounds could be readily confirmed. Application of the method was demonstrated by the microscale identification of two conjugated triene and one conjugated diene components from extracts of the sex pheromone gland of the saturniid moth Automeris cecrops pamina.     

Heteronuclear diatomic transition-metal cluster ions in the gas phase: Reactivity and thermochemistry of AgFe+

The gas-phase chemistry of AgFe⁺ was studied by using Fourier transform ion cyclotron resonance mass spectrometry. AgFe⁺ is unreactive with alkanes but reacts with cyclic and linear (C4–C8) alkenes. The primary reactions are dominated by dehydrogenation and condensation. In addition, cluster splitting is observed in the reaction of AgFe⁺ with benzene. Secondary reactions generally involve cluster splitting with the loss of Ag, although AgFeC₅H ₆ ⁺ is observed to dehydrogenate cyclopentene to yield AgFeC₁₀H ₁₂ ⁺ . Ion-molecule reactions, collision-induced dissociation, and photodissociation experiments were used to determine the bond energiesD°(Fe⁺–Ag)=53±7 kcal/mol andD°(Ag⁺–Fe)=46±7 kcal/mol. These values in turn were used to calculateH _f (AgFe⁺)=296±7 kcal/mol andIP(AgFe)=6.5±0.3 eV. Related chemical and physical properties of CuFe⁺ are presented for comparison.     

Adaptations for pressure and temperature effects on loop motion in Escherichia coli and Moritella profunda dihydrofolate reductase

ABSTRACT

Determining how enzymes in piezophilic microbes function at high pressure can give insights into how life adapts to living at high pressure. Here, the effects of pressure and temperature on loop motions of Escherichia coli (Ec) and Moritella profunda (Mp) dihydrofolate reductase (DHFR) are compared via molecular dynamics simulations at combinations of the growth temperature and pressure of the two organisms. Analysis indicates that a flexible CD loop in MpDHFR is an adaptation for cold because it makes the adenosine binding subdomain more flexible. Also, analysis indicates that the Thr113-Glu27 hydrogen bond in MpDHFR is an adaptation for high pressure because it provides flexibility within the loop subdomain compared to the very strong Thr113-Asp27 hydrogen bond in EcDHFR, and affects the correlation of the Met20 and GH loops. In addition, the results suggest that temperature might affect external loops more strongly while pressure might affect motion between elements within the protein.     

Evaluation of liposomal delivery of antisense oligonucleotide by capillary electrophoresis with laser-induced fluorescence detection

Two widely used commercial cationic liposome formulations, Lipofectamine and Escort, were evaluated for drug delivery efficacy with capillary electrophoresis coupled with laser-induced fluorescence detection using a fluorescein conjugated 2'-O-methyl-phosphorothioate (Me-PS) antisense oligonucleotide and the HeLa cell line. Binding constants were estimated by monitoring changes in the electrophoretic mobility of the oligonucleotide with the liposome solution in the running buffer. From these changes in mobility, the binding constants for Lipofectamine and Escort liposomes with Me-PS oligomer were estimated to be 1139 and 590 M(-1), respectively. Additionally, intracellular concentrations and gene expression were quantified for the liposome formulations.     

Signal Processing for Large Bandwidth and Long Duration Waveform SAR

We first show that for some kinds of signals a bandwidth and time duration reduction technique can be used to simulate waveform distortions caused by moving targets, that is, it is correct to measure the waveform distortions at very large TB with relatively small by reducing TB and increasing while keeping TB unchanged, where T is the duration of the transmitted signal, B is the bandwidth and is the relative speed of targets. We then study the waveform distortions in SAR signals caused by moving antenna. Based on the bandwidth and time duration reduction technique, a lot of time and memory are saved in simulations. We then confirm by simulations that waveform distortions do pose problems when processing very large bandwidth and long duration SAR data using conventional SAR processing methods. Finally we propose the concepts of wideband and narrowband processing of SAR data. Models are set up for wideband and narrowband SAR data processing, and new methods are presented for reconstructing targets using the proposed models. Simulations show that the methods can improve the quality of the simulated SAR images.