A Study of the Mechanism of Action of Zervamicin IIB Peptide Antibiotic by Molecular Dynamics Simulation

We model mechanism of action of a channel-forming peptide antibiotic, zervamicin IIB, by molecular dynamics (MD) simulation. Interaction of this peptide with neutral and negatively charged lipid bilayers is investigated. It is found that charge of membrane surface influences the orientation of zervamicin IIB molecule, that may in turn effect its permeation into the membrane. On this basis we propose modifications to ZrvIIB structure that may increase its affinity towards the prokaryotic cellular membrane. Zervamicin IIB transmembrane channels are modeled as bundles consisting of 4, 5 and 6 individual peptide monomers. Our results suggest that four monomers don’t form a stable water-filled ion channel. Thus the channel with the least number of monomers (and the lowest conductance level by literature data) is a pentamer

Mistletoe lectin dissociates into catalytic and binding subunits before translocation across the membrane to the cytoplasm

AbstractHybridomas producing monoclonal antibodies (mAbs) against the mistletoe lectin A-chain (MLA) were obtained to investigate the intracellular routing and translocation of ribosome-inactivating proteins. Anti-MLA mAb MNA5 did not bind the holotoxin but interacted with isolated MLA. This epitope was not recognized upon MLA denaturation or conjugation of MLA with the ricin binding subunit (RTB). Furthermore, the mAbs did not appreciably react with a panel of MLA synthetic octapeptides linked to the surface of polyethylene pins. A study of the cytotoxicity of mistletoe lectin, ricin, and chimeric toxin MLA/RTB for the hybridomas revealed that interchain disulfide bond reduction and subunit dissociation are required for cytotoxic activity of mistletoe lectin

Abstract OR-3: Integrative Structural Study of the Complex of Snake Toxin WTX with α7-type Nicotinic Acetylcholine Receptor

Background: Nicotinic acetylcholine receptors are ligand-gated ion channels present in the nervous system, epithelium, and the immune system. The α7-type nicotinic receptor (α7-nAChR) is a homopentameric membrane protein containing five ligand binding sites located at the interface between subunits in the extracellular domain of the receptor. α7-nAChR is considered a promising target for the treatment of cancer and cognitive dysfunction in Alzheimer's disease, schizophrenia, and depression. WTX is a non-conventional three-finger neurotoxin from the Naja kaouthia venom inhibiting α7-nAChR. WTX structure consists of three loops protruding from the “head” (core) stabilized by a system of disulfide bonds. Methods: The complex of the α7-nAChR extracellular domain with a recombinant analogue of WTX was studied by cryo-electron microscopy. The structure of the complex of full-length α7-nAChR with the toxin in the membrane environment was reconstructed by in silico molecular modeling. Interaction of WTX with the lipid membrane was confirmed by NMR-spectroscopy. Results: Analysis of electronic images confirmed the homopentameric organization of the extracellular domain with a diameter of ~ 9 nm and a height of ~ 7 nm. On the electron density map, additional regions corresponding to five WTX molecules located at the intersubunit interfaces of the domain were observed. Fitting the known spatial structures of the extracellular domain and the WTX toxin into the obtained electron density made it possible to reconstruct the structure of the complex (although with a low resolution of ~ 8 Ǻ due to the predominant orientation of particles in the ice) and to determine the topology of the toxin-receptor interaction. It was revealed that WTX interacts with the extracellular domain of α7-nAChR by the loop II, while the loop I and the toxin’s head seem to interact with the surface of the lipid membrane surrounding the receptor. Model of the complex of the full-length α7-nAChR receptor with WTX in the membrane environment corresponding to the neuronal membrane was constructed using computer simulation methods. Molecular dynamics for >1500 ns confirmed the stability of the complex. The predicted membrane-active site of the WTX molecule includes residues Lys13 and Arg18. The study of WTX and its mutants Lys13Ala and Arg18Ala by NMR-spectroscopy confirmed the importance of these residues for interaction with lipid membrane. Conclusion: Interaction mode of non-conventional neurotoxins with nAChR has been determined for the first time

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Search for lepton-flavor violating decays of the Higgs boson in the mu tau and e tau final states in proton-proton collisions at root s=13 TeV

A search is presented for lepton-flavor violating decays of the Higgs boson to mu t and et. The dataset corresponds to an integrated luminosity of 137 fb(-1) collected at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. No significant excess has been found, and the results are interpreted in terms of upper limits on lepton-flavor violating branching fractions of the Higgs boson. The observed (expected) upper limits on the branching fractions are, respectively, B(H -> mu t) e tau) < 0.22(0.16)% at 95% confidence level.Peer reviewe

Measurement of the top quark mass using events with a single reconstructed top quark in pp collisions at root s=13 TeV

Abstract:A measurement of the top quark mass is performed using a data sample en-riched with single top quark events produced in thetchannel. The study is based on proton-proton collision data, corresponding to an integrated luminosity of 35.9 fb−1, recorded at√s= 13TeV by the CMS experiment at the LHC in 2016. Candidate events are selectedby requiring an isolated high-momentum lepton (muon or electron) and exactly two jets,of which one is identified as originating from a bottom quark. Multivariate discriminantsare designed to separate the signal from the background. Optimized thresholds are placedon the discriminant outputs to obtain an event sample with high signal purity. The topquark mass is found to be172.13+0.76−0.77GeV, where the uncertainty includes both the sta-tistical and systematic components, reaching sub-GeV precision for the first time in thisevent topology. The masses of the top quark and antiquark are also determined separatelyusing the lepton charge in the final state, from which the mass ratio and difference aredetermined to be0.9952+0.0079−0.0104and0.83+1.79−1.35GeV, respectively. The results are consistentwithCPTinvariance