In this paper, we explore the possibility that a light dilaton can be the first sign of new physics at the LHC. The dilaton could emerge in approximate scale invariant UV completions of the SM as the Goldstone boson associated with the spontaneous breaking of the scale invariance. We study in detail the phenomenology of the dilaton at the LHC in the mass range of [10-300] GeV including the case where the dilaton can mix with the SM Higgs boson, leading to an interesting interplay between direct and indirect constraints. A possibility that the dilaton acts as a portal to a dark sector is also considered. As a minimal realization, the dark sector includes a dark photon lighter than the dilaton implying sizeable missing energy signatures. Several simplified benchmark models that can encode different UV completions are discussed, for which we scrutinize the current and future LHC reach.

A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) has collected several data sets from industry and added in-house data sets that may be used for this purpose (). CSAR has currently obtained data from Abbott, GlaxoSmithKline, and Vertex and is working on obtaining data from several others. Combined with our in-house projects, we are providing a data set consisting of 6 protein targets, 647 compounds with biological affinities, and 82 crystal structures. Multiple congeneric series are available for several targets with a few representative crystal structures of each of the series. These series generally contain a few inactive compounds, usually not available in the literature, to provide an upper bound to the affinity range. The affinity ranges are typically 3–4 orders of magnitude per series. For our in-house projects, we have had compounds synthesized for biological testing. Affinities were measured by Thermofluor, Octet RED, and isothermal titration calorimetry for the most soluble. This allows the direct comparison of the biological affinities for those compounds, providing a measure of the variance in the experimental affinity. It appears that there can be considerable variance in the absolute value of the affinity, making the prediction of the absolute value ill-defined. However, the relative rankings within the methods are much better, and this fits with the observation that predicting relative ranking is a more tractable problem computationally. For those in-house compounds, we also have measured the following physical properties: logD, logP, thermodynamic solubility, and pKa. This data set also provides a substantial decoy set for each target consisting of diverse conformations covering the entire active site for all of the 58 CSAR-quality crystal structures. The CSAR data sets (CSAR-NRC HiQ and the 2012 release) provide substantial, publically available, curated data sets for use in parametrizing and validating docking and scoring methods.

The development of a two-step approach for multiscale modeling of macromolecular conformational changes is based on recent developments in rigidity and elastic network theory. In the first step, static properties of the macromolecule are determined by decomposing the molecule into rigid clusters by using the graph-theoretical approach FIRST and an all-atom representation of the protein. In this way, rigid clusters are not limited to consist of residues adjacent in sequence or secondary structure elements as in previous studies. Furthermore, flexible links between rigid clusters are identified and can be modeled as such subsequently. In the second step, dynamical properties of the molecule are revealed by the rotations-translations of blocks approach (RTB) using an elastic network model representation of the coarse-grained protein. In this step, only rigid body motions are allowed for rigid clusters, whereas links between them are treated as fully flexible. The approach was tested on a data set of 10 proteins that showed conformational changes on ligand binding. For efficiency, coarse-graining the protein results in a remarkable reduction of memory requirements and computational times by factors of 9 and 27 on average and up to 25 and 125, respectively. For accuracy, directions and magnitudes of motions predicted by our approach agree well with experimentally determined ones, despite embracing in extreme cases >50% of the protein into one rigid cluster. In fact, the results of our method are in general comparable with when no or a uniform coarse-graining is applied; and the results are superior if the movement is dominated by loop or fragment motions. This finding indicates that explicitly distinguishing between flexible and rigid regions is advantageous when using a simplified protein representation in the second step. Finally, motions of atoms in rigid clusters are also well predicted by our approach, which points to the need to consider mobile protein regions in addition to flexible ones when modeling correlated motions.

Soluble guanylyl/guanylate cyclase (sGC) converts GTP to cGMP after binding nitric oxide, leading to smooth muscle relaxation and vasodilation. Impaired sGC activity is common in cardiovascular disease and sGC stimulatory compounds are greatly sought. sGC is a 150 kDa heterodimeric protein with two H-NOX domains (one with heme, one without), two PAS domains, a coiled-coil domain and two cyclase domains. Binding of NO to the sGC heme leads to proximal histidine release and stimulation of catalytic activity. To begin understanding how binding leads to activation, we examined truncated sGC proteins from Manduca sexta (tobacco hornworm) that bind NO, CO and stimulatory compound YC-1, but lack the cyclase domains. We determined the overall shape of truncated Ms sGC using analytical ultracentrifugation and small angle X-ray scattering (SAXS), revealing an elongated molecule 115 Å by 90 Å by 75 Å. Binding of NO, CO or YC-1 had little effect on shape. Using chemical cross-linking and tandem mass spectrometry, we identified 20 intermolecular contacts, allowing us to fit homology models of the individual domains into the SAXS-derived molecular envelope. The resulting model displays a central parallel coiled-coil platform upon which the H-NOX and PAS domains are assembled. The β1 H-NOX and α1 PAS domains are in contact and form the core signaling complex, while the α1 H-NOX domain can be removed without significant effect on ligand binding or overall shape. Removal of 21 residues from the C-terminus yields a protein with dramatically increased proximal histidine release rates upon NO binding.

A model of vector dark matter that communicates with the Standard Model only through gravitational interactions has been investigated. It has been shown in detail how does the canonical quantization of the vector field in varying FLRW geometry implies a tachyonic enhancement of some of its momentum modes. Approximate solutions of the mode equation have been found and verified against exact numerical ones. De Sitter geometry has been assumed during inflation while after inflation a non-standard cosmological era of reheating with a generic equation of state has been adopted which is followed by the radiation-dominated universe. It has been shown that the spectrum of dark vectors produced gravitationally is centered around a characteristic comoving momentum k⋆ that is determined in terms of the mass of the vector mX, the Hubble parameter during in- flation HI, the equation of state parameter w and the efficiency of reheating γ. Regions in the parameter space consistent with the observed dark matter relic abundance have been determined, justifying the gravitational production as a viable mechanism for vector dark matter. The results obtained in this paper are applicable within various possible models of inflation/reheating with non-standard cosmology parametrized effectively by the corresponding equation of state and efficiency of reheating.