On the HSL-flow

We introduce a natural geometric fourth order flow associated to Hamiltonian stationary submanifolds in Kähler–Einstein manifolds. Afterwards we study some of its properties and show short-time existence. In case of Hamiltonian stationary submanifolds with bounded second fundamental form evolving in flat space we obtain an existence time estimate (Theorem 3.7).     

Stable reduction of curves and tame ramification

We study stable reduction of curves in the case where a tamely ramified base extension is sufficient. If X is a smooth curve defined over the fraction field of a strictly henselian discrete valuation ring, there is a criterion, due to Saito, that describes precisely, in terms of the geometry of the minimal model with strict normal crossings of X, when a tamely ramified extension suffices in order for X to obtain stable reduction. For such curves we construct an explicit extension that realizes the stable reduction, and we furthermore show that this extension is minimal. We also obtain a new proof of Saito’s criterion, avoiding the use of ℓ-adic cohomology and vanishing cycles.     

Liquid water structure from X-ray absorption and emission,NMR shielding and X-ray diffraction

Here we investigate to what extent X-ray absorption(XAS) and emission(XES) spectroscopy, the oxygen-oxygen radial distribution function and σ(~1H) and σ(~(17)O) NMR shielding can be represented by a common set of model structures of liquid water. This is done by using a Monte Carlo-based fitting technique which fits the spectra based on a library of ～1400 precomputed spectra and assigns weights to contributions from different model structures. These are then used to reweight the contributions from the structures in the library to reveal classes of structures that are over-or under-represented in the library. The goal is to include different experimental data sets which are sensitive to different aspects of liquid water structure and thus narrow down which types of structures must exist in the real liquid.     

A Short Synthesis of (+)-Brefeldin C through Enantioselective Radical Hydroalkynylation

A very concise total synthesis of (+)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentane stereocenters in a single step. The use of a furan substituent allows a high trans diastereoselectivity to be achieved during the radical process and it contains the four carbon atoms C1–C4 of the natural product in an oxidation state closely related to the one of the target molecule. The eight-step synthesis requires six product purifications and it provides (+)-brefeldin C in 18 % overall yield.     

The Active Site of a Prototypical “Rigid” Drug Target is Marked by Extensive Conformational Dynamics

Drug discovery, in particular optimization of candidates using medicinal chemistry, is generally guided by structural biology. However, for optimizing binding kinetics, relevant for efficacy and off-target effects, information on protein motion is important. Herein, we demonstrate for the prototypical textbook example of an allegedly “rigid protein” that substantial active-site dynamics have generally remained unrecognized, despite thousands of medicinal-chemistry studies on this model over decades. Comparing cryogenic X-ray structures, solid-state NMR on micro-crystalline protein at room temperature, and solution NMR structure and dynamics, supported by MD simulations, we show that under physiologically relevant conditions the pocket is in fact shaped by pronounced open/close conformational-exchange dynamics. The study, which is of general significance for pharmacological research, evinces a generic pitfall in drug discovery routines.