Influence of conformational fluctuations on enzymatic activity: modelling the functional motion of beta-secretase

Considerable insight into the functional activity of proteins and enzymes can be obtained by studying the low-energy conformational distortions that the biopolymer can sustain. We carry out the characterization of these large scale structural changes for a protein of considerable pharmaceutical interest, the human $\beta$-secretase. Starting from the crystallographic structure of the protein, we use the recently introduced beta-Gaussian model to identify, with negligible computational expenditure, the most significant distortion occurring in thermal equilibrium and the associated time scales. The application of this strategy allows to gain considerable insight into the putative functional movements and, furthermore, helps to identify a handful of key regions in the protein which have an important mechanical influence on the enzymatic activity despite being spatially distant from the active site. The results obtained within the Gaussian model are validated through an extensive comparison against an all-atom Molecular Dynamics simulation.Comment: To be published in a special issue of J. Phys.: Cond. Mat. (Bedlewo Workshop

Measurement and application of electron stripping of ultrarelativistic 208Pb81+^{208}\textrm{Pb}^{81+}

New measurements of the stripping cross-section for ultrarelativistic hydrogen-like lead ions passing through aluminium and silicon have been performed at the Advanced Wakefield experiment at CERN. Agreement with existing measurements and theory has been obtained. Improvements in terms of electron beam quality and ion beam diagnostic capability, as well as further applications of such an electron beam, are discussed

MEG Upgrade Proposal

We propose the continuation of the MEG experiment to search for the charged lepton flavour violating decay (cLFV) \mu \to e \gamma, based on an upgrade of the experiment, which aims for a sensitivity enhancement of one order of magnitude compared to the final MEG result, down to the $6 \times 10^{-14}$ level. The key features of this new MEG upgrade are an increased rate capability of all detectors to enable running at the intensity frontier and improved energy, angular and timing resolutions, for both the positron and photon arms of the detector. On the positron-side a new low-mass, single volume, high granularity tracker is envisaged, in combination with a new highly segmented, fast timing counter array, to track positron from a thinner stopping target. The photon-arm, with the largest liquid xenon (LXe) detector in the world, totalling 900 l, will also be improved by increasing the granularity at the incident face, by replacing the current photomultiplier tubes (PMTs) with a larger number of smaller photosensors and optimizing the photosensor layout also on the lateral faces. A new DAQ scheme involving the implementation of a new combined readout board capable of integrating the diverse functions of digitization, trigger capability and splitter functionality into one condensed unit, is also under development. We describe here the status of the MEG experiment, the scientific merits of the upgrade and the experimental methods we plan to use.Comment: A. M. Baldini and T. Mori Spokespersons. Research proposal submitted to the Paul Scherrer Institute Research Committee for Particle Physics at the Ring Cyclotron. 131 Page

The AWAKE Electron Spectrometer

The AWAKE experiment at CERN aims to use a proton driven plasma wakefield to accelerate electrons from 10–20 MeV up to GeV energies in a 10 m plasma cell. We present the design of the magnetic spectrometer which will measure the electron energy distribution. Results from the calibration of the spectrometer's scintillator and optical system are presented, along with a study of the backgrounds generated by the 400 GeV SPS proton beam

Simulations of events for the LUX-ZEPLIN (LZ) dark matter experiment

The LUX-ZEPLIN dark matter search aims to achieve a sensitivity to the WIMP-nucleon spin-independent cross-section down to (1–2)×10−12 pb at a WIMP mass of 40 GeV/c2. This paper describes the simulations framework that, along with radioactivity measurements, was used to support this projection, and also to provide mock data for validating reconstruction and analysis software. Of particular note are the event generators, which allow us to model the background radiation, and the detector response physics used in the production of raw signals, which can be converted into digitized waveforms similar to data from the operational detector. Inclusion of the detector response allows us to process simulated data using the same analysis routines as developed to process the experimental data

Projected sensitivity of the LUX-ZEPLIN experiment to the 0νββ decay of Xe 136

The LUX-ZEPLIN (LZ) experiment will enable a neutrinoless double β decay search in parallel to the main science goal of discovering dark matter particle interactions. We report the expected LZ sensitivity to Xe136 neutrinoless double β decay, taking advantage of the significant (>600 kg) Xe136 mass contained within the active volume of LZ without isotopic enrichment. After 1000 live-days, the median exclusion sensitivity to the half-life of Xe136 is projected to be 1.06×1026 years (90% confidence level), similar to existing constraints. We also report the expected sensitivity of a possible subsequent dedicated exposure using 90% enrichment with Xe136 at 1.06×1027 years

Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa

Antibiotic-resistant bacteria rapidly spread in clinical and natural environments and challenge our modern lifestyle. A major component of defense against antibiotics in Gram-negative bacteria is a drug permeation barrier created by active efflux across the outer membrane. We identified molecular determinants defining the propensity of small peptidomimetic molecules to avoid and inhibit efflux pumps in Pseudomonas aeruginosa, a human pathogen notorious for its antibiotic resistance.Combining experimental and computational protocols, we mapped the fate of the compounds from structure-activity relationships through their dynamic behavior in solution, permeation across both the inner and outer membranes, and interaction with MexB, the major efflux transporter of P. aeruginosa. We identified predictors of efflux avoidance and inhibition and demonstrated their power by using a library of traditional antibiotics and compound series and by generating new inhibitors of MexB. The identified predictors will enable the discovery and optimization of anti-bacterial agents suitable for treatment of P. aeruginosa infections