Algorithmic and Technical Improvements for Next Generation Drug Design Software Tools

[eng] The pharmaceutical industry is actively looking for new ways of boosting the efficiency and effectiveness of their R&D programmes. The extensive use of computational modeling tools in the drug discovery pipeline (DDP) is having a positive impact on research performance, since in silico experiments are usually faster and cheaper that their real counterparts. The lead identification step is a very sensitive point in the DDP. In this context, Virtual high-throughput screening techniques (VHTS) work as a filtering mecha-nism that benefits the following stages by reducing the number of compounds to be tested experimentally. Unfortunately the simplifications applied in the VHTS docking software make them prone generate false positives and negatives. These errors spread across the rest of the DDP stages, and have a negative impact in terms of financial and time costs. In the Electronic and Atomic Protein Modelling group (Barcelona Supercomputing Center, Life Sciences department), we have developed the Protein Energy Landscape Exploration (PELE) software. PELE has demonstrated to be a good alternative to explore the conformational space of proteins and perform ligand-protein docking simulations. In this thesis we discuss how to turn PELE into a faster and more efficient tool by improving its technical and algorithmic features, so that it can be eventually used in VHTS protocols. Besides, we have addressed the difficulties of analyzing extensive data associated with massive simulation production. First, we have rewritten the software using C++ and modern software engineering techniques. As a consequence, our code base is now well organized and tested. PELE has become a piece of software which is easier to modify, understand, and extend. It is also more robust and reliable. The rewriting the code has helped us to overcome some of its previous technical limitations, such as the restrictions on the size of the systems. Also, it has allowed us to extend PELE with new solvent models, force fields, and types of biomolecules. Moreover, the rewriting has make it possible to adapt the code in order to take advantage of new parallel architectures and accelerators obtaining promising speedup results. Second, we have improved the way PELE handles protein flexibility by im-plemented and internal coordinate Normal Mode Analysis (icNMA) method. This method is able to produce more energy favorable perturbations than the current Anisotropic Network Model (ANM) based strategy. This has allowed us to eliminate the unneeded relaxation phase of PELE. As a consequence, the overall computational performance of the sampling is significantly improved (-5-7x). The new internal coordinates-based methodology is able to capture the flexibility of the backbone better than the old method and is in closer agreement to molecular dynamics than the ANM-based method

Size and Shape Constraints of (486958) Arrokoth from Stellar Occultations

International audienceWe present the results from four stellar occultations by (486958) Arrokoth, the flyby target of the New Horizons extended mission. Three of the four efforts led to positive detections of the body, and all constrained the presence of rings and other debris, finding none. Twenty-five mobile stations were deployed for 2017 June 3 and augmented by fixed telescopes. There were no positive detections from this effort. The event on 2017 July 10 was observed by the Stratospheric Observatory for Infrared Astronomy with one very short chord. Twenty-four deployed stations on 2017 July 17 resulted in five chords that clearly showed a complicated shape consistent with a contact binary with rough dimensions of 20 by 30 km for the overall outline. A visible albedo of 10% was derived from these data. Twenty-two systems were deployed for the fourth event on 2018 August 4 and resulted in two chords. The combination of the occultation data and the flyby results provides a significant refinement of the rotation period, now estimated to be 15.9380 ± 0.0005 hr. The occultation data also provided high-precision astrometric constraints on the position of the object that were crucial for supporting the navigation for the New Horizons flyby. This work demonstrates an effective method for obtaining detailed size and shape information and probing for rings and dust on distant Kuiper Belt objects as well as being an important source of positional data that can aid in spacecraft navigation that is particularly useful for small and distant bodies