Novel bioactive molecules can be rationally designed by growing and linking small fragments. Because fragments are fast and promiscuous, it is common to have contradictory hit results between different experimental screening techniques. Here, we simultaneously determine fragment binding poses, affinities, and kinetics on a focused library of 42 fragments against the serine protease factor Xa using multimillisecond molecular dynamics simulations. We predict experimental poses of 12 over 15 S1 crystal structures, and affinities are recovered for 4 out of 6. A kinetic map of protein cavities is computed in terms of on- and off-rates as well as insights into secondary ligand poses. The results suggest that the approach can be useful to recapitulate discordant fragment screening data.

The design and use of a metadata-driven data repository for research data management is described. Metadata is collected automatically during the submission process whenever possible and is registered with DataCite in accordance with their current metadata schema, in exchange for a persistent digital object identifier. Two examples of data preview are illustrated, including the demonstration of a method for integration with commercial software that confers rich domain-specific data analytics without introducing customisation into the repository itself.

Molecular simulations produce very highdimensional data-sets with millions of data points. As analysis methods are often unable to cope with so many dimensions, it is common to use dimensionality reduction and clustering methods to reach a reduced representation of the data. Yet these methods often fail to capture the most important features necessary for the construction of a Markov model. Here we demonstrate the results of various dimensionality reduction methods on two simulation data-sets, one of protein folding and another of protein-ligand binding. The methods tested include a k-means clustering variant, a non-linear auto encoder, principal component analysis and tICA. The dimension-reduced data is then used to estimate the implied timescales of the slowest process by a Markov state model analysis to assess the quality of the projection. The projected dimensions learned from the data are visualized to demonstrate which conformations the various methods choose to represent the molecular process.

Acute epiglottitis is a rare condition, especially in adults, largely owing to the widespread vaccination against Haemophilus influenzae. Traumatic epiglottitis as a result of thermal or caustic insults is documented. Epiglottic abscess formation is described as a sequela of epiglottitis in some cases. The development of epiglottic abscess from epiglottitis secondary to radiotherapy has previously been described in the literature; however, there are no reports of fatalities due to epiglottic abscess after radiotherapy. We present an unusual case of an adult sudden death due to epiglottic abscess formation subsequent to radiotherapy for laryngeal squamous cell carcinoma.