Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods

AbstractBinding of blockers to the human voltage-gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds

Structure–activity relationship for extracellular block of K+ channels by tetraalkylammonium ions

AbstractExternal tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions

Characterisation of the dip-bump structure observed in proton-proton elastic scattering at root s=8 TeV

We describe an analysis comparing the p (p) over bar elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeVusing a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of root s = 1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4s level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4s and 4.6s. The combined significance is larger than 5 sigma and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.Peer reviewe

Odderon Exchange from Elastic Scattering Differences between pp and p(p)over-bar Data at 1.96 TeV and from pp Forward Scattering Measurements

We describe an analysis comparing the p (p) over bar elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeVusing a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of root s = 1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4s level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4s and 4.6s. The combined significance is larger than 5 sigma and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.Peer reviewe

Tests of a Roman Pot Prototype for the TOTEM Experiment

3 pages, 8 figures, proceedings of PAC05, Knoxville, Tennessee, USA, May 2005The TOTEM collaboration has developed and tested the first prototype of its Roman Pots to be operated in the LHC. TOTEM Roman Pots contain stacks of 10 silicon detectors with strips oriented in two orthogonal directions. To measure proton scattering angles of a few microradians, the detectors will approach the beam centre to a distance of 10 sigma + 0.5 mm (= 1.3 mm). Dead space near the detector edge is minimised by using two novel "edgeless" detector technologies. The silicon detectors are used both for precise track reconstruction and for triggering. The first full-sized prototypes of both detector technologies as well as their read-out electronics have been developed, built and operated. The tests took place first in a fixed-target muon beam at CERN's SPS, and then in the proton beam-line of the SPS accelerator ring. We present the test beam results demonstrating the successful functionality of the system despite slight technical shortcomings to be improved in the near future.Peer reviewe

TOTEM Physics

This article discusses the physics programme of the TOTEM experiment at the LHC. A new special beam optics with beta* = 90 m, enabling the measurements of the total cross-section, elastic pp scattering and diffractive phenomena already at early LHC runs, is explained. For this and the various other TOTEM running scenarios, the acceptances of the leading proton detectors and of the forward tracking stations for some physics processes are described.Peer reviewe

First Search for Exclusive Diphoton Production at High Mass with Tagged Protons in Proton-Proton Collisions at root s=13 TeV

A search for exclusive two-photon production via photon exchange in proton-proton collisions, pp -> p gamma gamma p with intact protons, is presented. The data correspond to an integrated luminosity of 9.4 fb(-1) collected in 2016 using the CMS and TOTEM detectors at a center-of-mass energy of 13 TeVat the LHC. Events are selected with a diphoton invariant mass above 350 GeVand with both protons intact in the final state, to reduce backgrounds from strong interactions. The events of interest are those where the invariant mass and rapidity calculated from the momentum losses of the forward-moving protons match the mass and rapidity of the central, two-photon system. No events are found that satisfy this condition. Interpreting this result in an effective dimension-8 extension of the standard model, the first limits are set on the two anomalous four-photon coupling parameters. If the other parameter is constrained to its standard model value, the limits at 95% confidence level are vertical bar zeta(1)vertical bar < 2.9 x 10(-1)3 GeV-4 and vertical bar zeta(2)vertical bar < 6.0 x 10(-13) GeV-4.Peer reviewe

Exploring Ligand Binding in HIV-1 Protease and K+ Channels Using Computational Methods

Understanding protein-ligand interactions is highly important in drug development. In the present work the objective is to comprehend the link between structure and function using molecular modelling. Specifically, this thesis has been focused on implementation of receptor flexibility in molecular docking and studying structure-activity relationships of potassium ion channels and their blockers. In ligand docking simulations protein motion and heterogeneity of structural waters are approximated using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. Two weighted average methods permit consistent and accurate ligand docking using a single grid representation of the target protein structures. Quaternary ammonium ions (QAIs) are well known K+ channel blockers. Conformations around C–N bonds at the quaternary centre in tetraalkylammonium ions in water solution are investigated using quantum mechanical methods. Relative solvation free energies of QAIs are further estimated from molecular dynamics simulations. The torsion barrier for a two-step interconversion between the conformations D2d and S4 is calculated to be 9.5 kcal mol–1. Furthermore D2d is found to be more stable than the S4 conformation which is in agreement with experimental studies. External QAI binding to the K+ channel KcsA is also studied. Computer simulations and relative binding free energies of the KcsA complexes with QAIs are calculated. This is done with the molecular dynamics free energy perturbation approach together with automated ligand docking. In agreement with experiment, the Et4N+ blocker in D2d symmetry has better binding than the other QAIs. Binding of blockers to the human cardiac hERG potassium channel is studied using a combination of homology modelling, automated docking and molecular dynamics simulations. The calculations reproduce the relative binding affinities of a set of drug derivatives very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. Hence, the derived model of hERG should be useful for further interpretations of structure-activity relationships

Male nurses and their experiences of nursing from a genderperspective : A review

Den manliga sjuksköterskan verkar inom ett kvinnligt kodat yrke, ett yrke som genomsyras av en genusordning vilken skapar hierarkiska skillnader och maktstrukturer. Av denna anledning var syftet med studien att undersöka manliga sjuksköterskors upplevelser av genusnormer omgivet sin yrkesroll och dess inverkan på yrkesutövningen. Metod: Metoden var en litteraturstudie. Nio artiklar med kvalitativ metod valdes ut och kvalitetsgranskades efter sökning Cinahl och PubMed. Artiklarna analyserades med hjälp av integrerad analys. Resultat: Resultatet visade att bland annat kollegors, närståendes och patienternas föreställningar kunde inverka på den manliga sjuksköterskan såväl inför som i sin yrkesutövning. Detta kunde grunda sig på mannens position i genusordningen samt hur mannen uppfattades ur genusperspektiv, vilket även bland annat kunde inverka på mötet med såväl patienter som kollegor. Slutsats: Slutsatsen är att så länge de rådande genusnormerna, genusordningen och förhållandet till den hegemoniska maskuliniteten gör sig gällande i samhället, kommer en förändring av yrkesrollen ur ett genusperspektiv vara svår att uppnå. Betydelsen av studien är att genusproblematik lyfts upp och belyses, något som resultatet visade inte gärna öppet diskuteras, men i och med denna studie möjliggörs

The future of green concrete : A study of the market for climate-improved concrete in relation to future limit values in climate declarations

Sverige har som mål att senast år 2045 inte ha några nettoutsläpp av växthusgaser till atmosfären. Ett område som diskuteras är byggsektorn och dess utsläpp, vilket har lett till åtgärder i form av införandet av klimatdeklarationer. Dessa ska revideras med krav i form av gränsvärden som förväntas implementeras senast år 2027. Ett område med betydande utsläpp inom byggsektorn är användandet av betong som material vid nybyggnation, varvid intresset av klimatförbättrade varianter har ökat drastiskt under senaste åren.  Denna studie genomförs i samarbete med Wallenstam där det övergripande målet är att identifiera hur marknaden för klimatförbättrad betong står sig gentemot de kommande gränsvärden som förväntas införas till klimatdeklarationer senast år 2027. Ett av målen är att genom en beräkning visa hur en byggnads klimatutsläpp påverkas vid ett användande av klimatförbättrad betong istället för traditionell betong, där ett referensprojekt från Wallenstam har använts. Arbetet ska även, genom en intervjustudie, redogöra för vilka förutsättningar leverantörer av klimatförbättrad betong står inför att ta fram klimatneutral betong. Även om vissa leverantörers produkter gav ett lägre klimatutsläpp än andra visade resultatet ingen större avvikelse hos någon av leverantörerna. Samtliga undersökta leverantörer har produkter som ger ett lägre klimatavtryck än det gränsvärde som är baserat på referensprojektet. Alla undersökta kombinationer av leverantörernas produkter visade ett resultat med en minskning på över 20% där kombinationen med lägst klimatavtryck, som enbart innehåller platsgjuten betong, visade en minskning av byggnadens totala utsläpp på 38.4%. Intervjustudien visade att implementering av CCS-teknik och andra alternativa bindemedel krävs för att nå en klimatneutral betong. Sweden aims to have zero net emissions of greenhouse gases by the year 2045. A major contributor to emissions is the construction sector, which has led to the introduction of climate declarations. These will be revised with requirements in the form of limit values that are expected to be implemented by the year 2027. As concrete accounts for a large part of the emissions from the construction sector, interest in climate-improved variants has increased significantly in recent years. This study is carried out in collaboration with Wallenstam, where the overall goal is to identify how the market for climate-improved concrete stands in relation to the future limit values that are expected to be introduced in climate declarations by the year 2027. One of the goals is to show how a building's climate emissions are affected by the use of climate-improved concrete instead of traditional concrete. For this, a reference project from Wallenstam has been used. The study will also, through an interview study, account for the conditions that suppliers of climate-improved concrete are facing to produce climate-neutral concrete. Although some suppliers' products had lower climate emissions than others, the results did not show any major deviation at any of the suppliers. All surveyed suppliers have products that have a lower climate footprint than the limit value based on the reference project. All examined combinations of the suppliers' products showed a result with a reduction of over 20%, where the combination with the lowest climate footprint, which only contains cast-in-place concrete, showed a reduction in the building's total emissions of 38.4%. The interview study showed that implementation of CCS technology and other alternative binders is required to reach a climate-neutral concrete