Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer’s disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments—huprine and rhein— that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable “floppy” pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors

Search for strongly interacting massive particles generating trackless jets in proton-proton collisions at s = 13 TeV

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton-proton collision data corresponding to an integrated luminosity of 16.1 fb - 1 , collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100 GeV are excluded and further sensitivity is explored towards higher masses

Evidence for Top Quark Production in Nucleus-Nucleus Collisions

Peer reviewe

Observation of the B-s(0) -> X(3872)phi Decay

Using a data sample of proton-proton collisions at root s = 13 TeV, corresponding to an integrated luminosity of 140 fb(-1) collected by the CMS experiment in 2016-2018, the B-s(0) -> X(3872)phi decay is observed. Decays into J/psi pi(+)pi(-) and K+K- are used to reconstruct, respectively, the X(3872) and phi. The ratio of the product of branching fractions B[B-s(0) -> X(3872)phi]B[X(3872) -> J/psi pi(+)pi(-)] to the product B[B-s(0) ->psi(2S)phi]B[psi(2S) -> J/psi pi(+)pi(-)] is measured to be [2.21 +/- 0.29(stat) +/- 0.17(syst)]%. The ratio B[B-s(0) -> X(3872)phi]/B[B-0 -> X(3872)K-0] is found to be consistent with one, while the ratio B[B-s(0) -> X(3872)phi]/B[B+-> X(3872)K+] is two times smaller. This suggests a difference in the production dynamics of the X(3872) in B-0 and B(0)s meson decays compared to B+. The reported observation may shed new light on the nature of the X(3872) particle.Peer reviewe

Observation of a New Excited Beauty Strange Baryon Decaying to Ξb- π+π-

The Ξb-π+π- invariant mass spectrum is investigated with an event sample of proton-proton collisions at s=13 TeV, collected by the CMS experiment at the LHC in 2016-2018 and corresponding to an integrated luminosity of 140 fb-1. The ground state Ξb- is reconstructed via its decays to J/ψΞ- and J/ψΛK-. A narrow resonance, labeled Ξb(6100)-, is observed at a Ξb-π+π- invariant mass of 6100.3±0.2(stat)±0.1(syst)±0.6(Ξb-) MeV, where the last uncertainty reflects the precision of the Ξb- baryon mass. The upper limit on the Ξb(6100)- natural width is determined to be 1.9 MeV at 95% confidence level. The low Ξb(6100)- signal yield observed in data does not allow a measurement of the quantum numbers of the new state. However, following analogies with the established excited Ξc baryon states, the new Ξb(6100)- resonance and its decay sequence are consistent with the orbitally excited Ξb- baryon, with spin and parity quantum numbers JP=3/2-

Measurement of the inclusive and differential Higgs boson production cross sections in the decay mode to a pair of τ Leptons in pp collisions at sqrt[s]=13 TeV

Measurements of the inclusive and differential fiducial cross sections of the Higgs boson are presented, using the τ lepton decay channel. The differential cross sections are measured as functions of the Higgs boson transverse momentum, jet multiplicity, and transverse momentum of the leading jet in the event, if any. The analysis is performed using proton-proton collision data collected with the CMS detector at the LHC at a center-of-mass energy of 13  TeV and corresponding to an integrated luminosity of 138  fb^{-1}. These are the first differential measurements of the Higgs boson cross section in the final state of two τ leptons. In final states with a large jet multiplicity or with a Lorentz-boosted Higgs boson, these measurements constitute a significant improvement over measurements performed in other final states

Search for dark matter produced in association with a Higgs boson decaying to a pair of bottom quarks in proton-proton collisions at root s=13TeV

A search for dark matter produced in association with a Higgs boson decaying to a pair of bottom quarks is performed in proton-proton collisions at a center-of-mass energy of 13 TeV collected with the CMS detector at the LHC. The analyzed data sample corresponds to an integrated luminosity of 35.9 fb(-1). The signal is characterized by a large missing transverse momentum recoiling against a bottom quark-antiquark system that has a large Lorentz boost. The number of events observed in the data is consistent with the standard model background prediction. Results are interpreted in terms of limits both on parameters of the type-2 two-Higgs doublet model extended by an additional light pseudoscalar boson a (2HDM+a) and on parameters of a baryonic Z simplified model. The 2HDM+a model is tested experimentally for the first time. For the baryonic Z model, the presented results constitute the most stringent constraints to date.Peer reviewe

A Deep Neural Network for Simultaneous Estimation of b Jet Energy and Resolution

We describe a method to obtain point and dispersion estimates for the energies of jets arising from b quarks produced in proton-proton collisions at an energy of s = 13 TeV at the CERN LHC. The algorithm is trained on a large sample of simulated b jets and validated on data recorded by the CMS detector in 2017 corresponding to an integrated luminosity of 41 fb - 1 . A multivariate regression algorithm based on a deep feed-forward neural network employs jet composition and shape information, and the properties of reconstructed secondary vertices associated with the jet. The results of the algorithm are used to improve the sensitivity of analyses that make use of b jets in the final state, such as the observation of Higgs boson decay to b b ¯

Search for the X(5568) State Decaying into B-s(0)pi(+/-) in Proton-Proton Collisions at root s=8 TeV

A search for resonancelike structures in the B-s(0)pi(+/-) invariant mass spectrum is performed using proton-proton collision data collected by the CMS experiment at the LHC at root s = 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The B-s(0) mesons are reconstructed in the decay chain B-s(0) -> J/Psi phi, with J/Psi -> mu(+) mu(-) and phi -> K+K-. The B-s(0)pi(+/-) invariant mass distribution shows no statistically significant peaks for different selection requirements on the reconstructed B-s(0) and pi(+/-) candidates. Upper limits are set on the relative production rates of the X(5568) and B-s(0) states times the branching fraction of the decay X(5568)(+/-) -> B-s(0)pi(+/-). In addition, upper limits are obtained as a function of the mass and the natural width of possible exotic states decaying into B-s(0)pi(+/-).Peer reviewe

Search for lepton flavour violating decays of a neutral heavy Higgs boson to μτ and eτ in proton-proton collisions at s√ = 13 TeV

A search for lepton flavour violating decays of a neutral non-standard-model Higgs boson in the μτ and eτ decay modes is presented. The search is based on proton-proton collisions at a center of mass energy s√ = 13 TeV collected with the CMS detector in 2016, corresponding to an integrated luminosity of 35.9 fb−1. The τ leptons are reconstructed in the leptonic and hadronic decay modes. No signal is observed in the mass range 200–900 GeV. At 95% confidence level, the observed (expected) upper limits on the production cross section multiplied by the branching fraction vary from 51.9 (57.4) fb to 1.6 (2.1) fb for the μτ and from 94.1 (91.6) fb to 2.3 (2.3) fb for the eτ decay modes