X-rays for Soft- Condensed Matter (X4SCM)

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Doc No: DLS-SACDISCo-X4SCM Issue: 1 Date: Nov 2020 Page: 1 of 26

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X-raysforSoft-CondensedMatter

(X4SCM)RedefiningtheBoundariesofTime-ResolvedSoft-CondensedMatter

Experiments:Ahighflux,simultaneousUSAXS/SAXS/WAXSinstrumentforsoftandbiologicalmaterials

PreparedforDiamondSAC/DISCODECEMBER2020

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1. AcknowledgementsThisexcitingproposalhasbeenunderpinnedbycollaborationandengagementacrossDiamond’sSoftCondensedMattercommunity.Atallstageswehavebroughttogetherinternalexpertiseincuttingedgebeamlinedevelopmentwith theresearchvisionofbothcurrentandprospectiveusersacrossabroadrangeofsectorsandfields.Thisteamhasco-developaproposalthatwebelievewillestablishaworldleadingSoftCondensedMatterecosystematDiamondtoenabletheambitionsofUKandinternationalscienceoverthenext20years.

ExternalChampions:GeoffMoggridge(UniversityofCambridge,UK)andNickBrooks(ImperialCollege,UK)

UserWorkingGroup(UWG)Members:

Pete Dowding (Infineum,Milton Hill, UK), Rachel Evans (University of Cambridge, UK), Marianne Liebi(ChalmersUniversityofTechnology,Sweden),HimadriGupta(QueenMaryUniversityofLondon,UK),JanIlavsky (Argonne National Laboratory, USA), Timothy Knowles (Cardiff University, UK), Yugi Sasaki(Univeristy of Tokyo, Japan), Clair Baldock (University ofManchester,UK), LucaPellegrini (University ofCambridge,UK),AnnelaSeddon(UniversityofBristol,UK),ArwenTyler(UniversityofLeeds,UK),NickTerrill(DiamondLightSource),AndySmith(DiamondLightSource),KatsuakiInoue(DiamondLightSource)andNathanCowieson(DiamondLightSource),KarenEdler(UniversityofBath,UK).

PublicWorkshops:

SCMDiamondIIWorkshop10Sep2018

Ourfirstuserworkshopfeatured3sessionscovering1)ImaginginSCM,2)MicrofluidicsinSCMand3)Time-resolvedstudiesinSCM.Speakersandtitlesarelistedbelow.

• SmallandBrightX-raybeamsforSAXS(NigelKirby,AustralianSynchrotron,Australia)

• CDMMPforImaging(BartKahr,NYU,USA)

• CellularInfraredMicroscopyatDiamondandDiamondII(LucaQuaroni,JagiollonianUniversity,Poland)

• UnlockingTerahertzDynamicsofPorousMaterialsatB22(Prof.Jin-ChongTan,Univ.Oxford)

• MicrofluidicsinSCM(NickBrooks,ImperialCollegeLondon,UK)

• MicrofluidicsandCD(JeromeCharmet,Univ.Warwick,UK)

• CatalysisatB22:PresentandFutureOpportunities(RussellHowe,Univ.Aberdeen,UK)

• MicrofluidicsDevelopmentsandApplicationsatSOLEIL(BenediktLassalle,SOLEIL,France)

• X-rayFoot-printingMassSpectrometry(XFMS)(PeterStockley,Univ.Leeds,UK)

• SAXSandMicrostructuresinArtificialHeartValves(GeoffMoggridge.Univ.Cambridge,UK)

• Complex EnzymeMechanisms Resolved on B22 using IRMicro-spectroscopy under ElectrochemicalControl(KylieVincent,Univ.Oxford,UK)

• IRImagine/CorrelativeStudies(RohitBhargava,UniversityofIllinoisatUrbana-Champaign,USA)

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X4SCMDiamondIIWorkshop23Oct2020

• IntroductiontoX4SCMandI22(RobRamboandNickTerrill,DiamondLightSource)

• Self-assemblyofnanostructuredmaterials–frommicellestoparticles(KarenEdler,Univ.ofBath,UK)

• SAXStensortomography:reconstructionandapplicationexamples(MarianneLiebi,EMPA,Switzerland)

• DiffractionX-rayTracking (DXT)–DynamicObservationofSingleMolecule in theBiologicalSystems(Prof.YujiSasaki,Univ.Tokyo,Japan)

• SynchrotronX-rayfootprintingofproteins:usinghydroxylradicalsolventaccessibilitytoinferstructuralconformation(CorieRalston,TheAdvancedLightSource,USA)

• ExtendedRangeUltraSmall-AngleX-ray,Small-Angle,andWide-AngleScatteringforFutureMaterialsDevelopment(JanIlavsky,ArgonneNationalLaboratory,USA)

X4SCMUWGSplitSteeringMeeting(part1)23Nov2020

X4SCMUWGSplitSteeringMeeting(part2)24Nov2020

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2. ExecutiveSummary(300words)Soft-condensed matter (SCM) science is a driver for continuing improvements in quality of life, withresearch in the molecular engineering of soft, biological and bio-inspired materials underpinningsustainable, targeted developments in foods, agriculture, polymers, additivemanufacturing, lubricants,personalcare,electronics,transportation,healthandmedicine.CriticaltothefunctionofSCMsystemsistheirabilitytoself-assembleformingdynamichierarchicalstructuresthatarepartiallyorderedonmolecularto micron length-scales. The science of controlling these structures serves as the basis for molecularmaterialengineering inSCM.SmallangleX-rayscattering (SAXS) is thede-facto technique forprovidingstructural insightson these systems,however, there isno instrument,worldwide, that canobserve theentiremolecular tomicron length scales in real-time. Our proposedX-rays for Soft-CondensedMatter(X4SCM)beamlinewillbeaworld-leadinginstrumentofferingthefirstcameratosimultaneouslyobservethemolecular-tomicron-scaleordering,structureanddynamics.

X4SCM will operate two modalities: HIERARCHY, using monochromatic X-rays for real-time structuralinvestigationscapturingmolecular tomicron length-scalesandSNAPSHOT,usinghigh-fluxnano-focusedand‘pink’X-raysforhigh-speed,time-resolvedstudiesenablingcutting-edgedynamicSCMmeasurementswithin theUK community, including single-moleculeDiffractedX-rayTracking (DXT), X-ray Foot-printingMassSpectrometry(XFMS)andpink-beamSAXS.

TheX4SCMbeamlinewilltransformtheUK’spositioninmaterialsengineeringandbiologicaldynamicsandtogetherwith theexisting IR,CDandSAXS instrumentsoffers a coherent suiteof capabilities accessingdecadesoflengthandtimescales.

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3. Scientificcase(10pagesmaxincl.figures)3.1 Introduction

SCM materials occur over a wide-range ofphysicalstatesthat include liquid,semi-solid,waxes, glasses and aerosols. ThesematerialscanbederivedfromnaturalsourcesbutSCMscience’s overarching goal is to design andengineerbespokematerials thatoftenmimicnatural materials1. Natural materials oftencontain complex arrangements of anunderlying nano-structured building block(Figure 1). It is generally accepted that thiscomplex hierarchical structure confers thedesiredstructure-functionrelationship.

TheSCMgroupoperatesauniqueecosystemoffourbeamlinesandassociatedexpertiseforSCM science co-located within the Diamondring: 1) B22 for infrared imaging andnanospectroscopy, 2) B23 for studying chiralsystems via UV circular dichroism (CD), andtwo SAXS beamlines I22 and B21. B21 is aphase III Diamond beamline that focuses onhigh-throughputsolution-statesamples.

Whilethesecomplementarybeamlinescoverawiderangeofprobelength-scalesandtime-scales(Figure2),thereisacriticalvoidinreal-timemeasurementtechniquesthatlinktheSCMmolecular-tonano-scaleinformationofferedbySAXS/WAXSexperimentsonI22(andtoacertainextentB21),toSAXSmappingcapability, and the IR and CD micron scale structural imaging offered by B22 and B23. Being able tosimultaneouslymeasurestructuringfromthemoleculartothemicronlength-scaleandlinkthiswithIR,CDand light microscopy is a criticaldevelopmentpriorityinbothacademicandindustrial soft material science andengineering.

B21 users are mainly structural biologistsperforming solution state SAXS frombiological macromolecules which hasallowed this beamline to pursue a mail-inservicestrategythatdramatically increasesthe number of experimental sessionsoffered per year2. In contrast, most SCMexperiments arebespokewith setup timesand measurements requiring days, andexperiments aimed at mapping bothcondition space and phase space that testsamples under a variety of compositions,extremetemperatureandpressureranges,andmechanicalstrains.Thisfundamentallylimits the available sessions per year; and

Figure1A)Themantisshrimp’sdactylforelegpunchesat~50mphwithenoughforcetobreak¼-inchglass.Thedactylcluband body armour,mainly composed of chitin, has evolved auniquestructurethatcanwithstandblowsencounteredduringmating competition. Can replicating the arrangement of thenanostructured chitin lead to better helmets? B) Trabecularbone image (left) shows a seemingly homogenous material.SAXStensortomographyrevealshiddenstructuresillustratinglocalizedarrangementoffibrilbundles.AdaptedfromLiebl,M.etal.,Nature(2015)527,349-352.

Figure2Accessibletime-scalesandlength-scalesofferedbythecurrentSCMportfolioandtheenvisagedcontinuousprobeecosystemenabledbyX4SCMinDiamond-II.

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consequently,theexperimentaldevelopmentsthatwillbeenabledbyDiamondII.Inaddition,SAXStensortomography(STT)3-5,isshowinghugepotentialandgrowthasflagshiptechniqueforI22thatmapsstructuralfeaturesin3-D(Figure1),thiscurrentlytakes1.5daysfora2x1x1mm3sampleandwhileDiamondIIwilldrivedownthesetimescales,theexpectedincreasedacademicandindustrialdemandforthistechnique,makesprovisionofanewSCMX-rayinstrumentanurgentpriority.

OurproposedX-raysforSoft-CondensedMatter(X4SCM)beamlinewilldirectlyaddresstheneedforlength-scaleconvergencebyofferingtime-resolvedexperimentssimultaneouslyobservingtheUSAXS,SAXSandWAXSregimes,whilealsoprovidingaccesstocuttingedgeSCMtechniquesandtacklingtheUK’scriticalneedforincreasedSCMX-rayinstrumentationcapacity.Theproposalisfullyalignedwiththelong-heldSCMcommunityneedsmadeclearbytheI22usergroup,B21andI22users,andalsothoseofourX4SCMUserWorkingGroupandusercommunitystatementsofsupport.

3.2 ScienceenabledbyX4SCM

OurcurrentSCMcapabilitiesallowtheSCMgrouptoprobechemicalcompositionsatsub-10nanometerresolution through infrared nanospectroscopy6,measure supramolecular chiral structures in thin-films7,andinvestigatepartiallydisorderedsystemswithsmall-andwide-angleX-rayscatteringtechniques2.OurvisionfortheSCMgroupistocompletethiscomplementofcapabilitiesbyprovidinganinstrumentthat1)gives a complete USAXS-to-WAXS measurement in a single exposure, 2) enables time-resolvedinvestigations of protein and polymer dynamics, 3) increases our experimental portfolio for in vivoexperimentsonlivingcellsand4)optimizeexperimentalcapabilitiesofI22namelyautomationofGISAXS,tomography and mapping. The X4SCM beamline will be unique in the world, providing a competitiveadvantagetoourusercommunities.Forindustry,X4SCMwouldbeasuitablesubstitutetoneutronSESANS

and ultra-small angle scattering measurementstherebyreducingmeasurementtimesfromhourstosecondsandthusdecreasingcostpermeasurement.Similarly, many structural hypotheses regardingprotein flexibility,conformationalchanges,enzymeormotormechanismscanfinallyberesolveddirectlythroughXFMSandDXT.

Our current instrumentation limitation can beappreciatedthroughtheartificialheartvalveworkofDr. Geoff Moggridge of the Structured MaterialsGroupofCambridgeUniversity.Forengineeringanartificial heart valve, the material must withstand~100,000open-closecyclesperdaywhereeachcycleis approximately one second, but the valvemovement occurs in 1/20th of a second. Over 10years, thebiomaterial durabilitymustbe sufficientfor ~500 million cycles while being biocompatiblewith the patient. Self-assembling, cylinder-formingblockcopolymershavebeenengineeredasadurablematerial for prosthetic heart valves. The triblockcopolymers have a “rubbery” middle that selfassembles with outer “glassy” ends forminghexagonalarrays.CurrentDiamondcapabilitieshaveachieved10millisecondtimeresolutionataspatialresolutionof10microns.Given thevalvesare300

Figure 3 A) adapted from Journal of AppliedPhysics122, 224304 (2017) B) adapted from SoftMatter, 2017, 13, 8756—8765. Dashed red-linesshows current smallest angle measurable duringSAXS/WAXSmeasurementatI22.

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microns thick, the current spatial resolution is insufficient for understanding how defects occur duringmanufacturingoruse.Theblockcopolymersformlayeredstructuresduringinjectionmouldingwheretheshearforcesduringflowdictatehowthehexagonalarraysorientandpack.Ithasbeenobservedthatdefectsareintrinsicstrainsintroducedintothematerialhypothesizedtoformfromshearforcesthatcausesubtlestructuralvariationsinthefinalannealedmaterial.Understandingandcontrollinghowthesedefectsariseduringprocessingiscriticaltomakingavalvewiththedesiredmechanicalproperties.Moreimportantly,detectingthesedefectsinvalvespriortouseisnotpossiblewithexistinginstrumentation.

HIERARCHY is the USAXS to WAXS camera modality of X4SCM. USAXS measurements complementcanonicalSAXSstudiesbyinformingonlengthscalesbetweensub-microntomicronscales8-10.AcompleteUSAXS-to-WAXSpicturewillfullydescribe,inreciprocalspace,lengthscalesstartingfromthemoleculartomicron level.Currently, I22,at fullextension, issuitable formeasuring featuresat100’s-of-nanometers.Thislengthscaleisidealfordiblockcopolymersandmicelle-likebuildingblocksofsoftmaterials.However,for many SCMmaterials assembled from large nano-structured particles, the evolution of mesoscopicfeatureswillnotbeviewableonI22(Figure3).

USAXS experiments at the Advanced Photon Source (APS, Chicago, IL, USA)11 and Spring-8 (HyogoPrefecture,Japan)clearlydemonstratedsignificantchangesinmesoscopicfeaturesoccurringasmaterialsarepushedout-of-equilibriumandthattheUSAXSwindowcontainssignificantinformation(Figure3).TheUSAXSinformationcanshowthepresenceofamicro-structureorthatthedilutelimitofanassemblyhasbeenreached12.USAXScanreveal thestructure factorsuggestinghowthenano-structured featuresarecorrelatedwithinthemicrostructure10-11,13-15.Furthermore,USAXSdescribesthewallthicknesses,radius-of-gyrationsandshapesofgrainswithinthematerial.UnderstandinghownanoscalefeaturescorrelatewithadesiredmaterialpropertyremainsagoalofSCMscience1.Recentprogressinlargescaleproductionofnano-structuredmaterialssuggeststhepromiseofsmart,designedmaterialsmaysoonbearealitybutitwill be a beamline that provides simultaneous USAXS-to-WAXS studies that will allow users to followstructuralcorrelationsovertherequisitelengthscales.

EmphasizedbyDr.JanIlavsky(9ID,AdvancedPhotonSource,USA),aUSAXScameranotonlyuncovershidden features but also inspires a rich set of hypotheses to the investigator16. USAXS studies onaerogels17attheAPSrevealedfundamentaldifferencesbetweendifferentaerogeldensitiesthatexplainedwhymechanicalpropertiesdroppedataspecificdensitythreshold.USAXSobservationsshowedthelocalmicrostructurecollapseswithintheaerogel leadingtovoidsandadropinmechanicalproperties.IntheabsenceofUSAXSinformation,theWAXS(crystalline-scale)andSAXS(nano-scale)informationwasconfoundingastherewerenocleardifferencesattheselengthscales.

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SNAPSHOT will exploit the highphoton flux provided by X4SCM, weexpect 1013 photons per second ofmonochromaticbeamandnearly1015photons per second in pink beam.These photon fluxes open newopportunities for time-resolvedstudiesatDiamond.Weproposetwonewusertechniques,DiffractedX-rayTracking (DXT)18 and X-ray Foot-printingMass Spectrometry (XFMS)19for studies in the micro- to milli-second. In addition, the high-framerate integrating detectors will allowreliablemeasurementsatslowertimescalesrelevanttomostSCMmaterials.

DXTisasinglemoleculetechniquethattracksthemotionsofgoldnanocrystal-labelled materials. An individually

labelledprotein that is transiently fixed to a surfacewill producea singlediffracted (1,1,1) spotwith apolychromaticX-raybeam.Asthegoldnanocrystalwobblesorrotates(amotiondirectlycorrelatedtotheinternalmotionsoftheprotein),thediffractedspotwillalsomove(Figure4).DXThasbeendevelopedatSpring-8 by Prof. Yuji Sasaski20 and applied to channel gating18, peptide binding by MHC-II complex21,chaperonins22-23, in vivo studies of antifreeze proteins in C. elegans24 and GPCR proteins expressed inHEK293cells25.In2019,wehavebeendevelopingDXTatDiamondwithProf.SasakiutilizingtheprototypeTristandetectorwhichtime-stampsphotoneventsat200nanosecondresolution.Wewereabletoshowthis detector is ideal for DXT. Recording single-molecule diffraction events will be subject to high-backgroundscatteringduetoair,Kaptonwindowsandcross-sectionalareaoftheilluminatingX-raybeam.OurinitialexperimentsonB16useda300micron-squaredbeam,X4SCMwillprovideanano-focusedpinkbeamtomasivelyreducebackground(>105).DXTprovidesadirectassessmentoftheprotein’sdegrees-of-freedomandishighlycomplementarytobioSAXS.

Figure4DXTexperimentperformedatB16withprototypeTristandetector.A.Motionsofgold-nanocrystallabelledproteinproducechangesinthetaandchiangles relative to X-ray direction. B. Coil-coiled protein sample where zinc-bindingmotifwasmutated.C.Motionsofindividualdiffractedspotsformstracks(redWT,bluemutant).Changesinchiandthetaproducedistributionmaps(D,E)whereadifferencemap(F)illustrateschangesinpreferredmotionsbetweenWTandmutant.

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WhileDXToffers adirect viualizationof single-moleculedynamics,XFMScan correlatedynamicsat thesequence level. XFMS examines the rate of synchrotron radiation-induced hydroxyl radical damage ofresiduesatmicrosecondtimescales26.Highaccuracymassspectrometry(MS)allowssitesofdamagedtobe specifically identified andmapped to a primary sequence, identifying solvent-accessibility. Biological

scienceissequencedriven,eventhe final step of solving a high-resolution structure by cryo-EMor MX is accomplished throughtheinterpretationoftheelectrondensityintermsoftherespectiveprimarysequence.This is justastrueforXFMS,thehighaccuracyMSallowsforatomicleveldetails(modifications) to be mappedontoaprimarysequenceunderabroad set of experimentalconditions (in solution, in vivo,and semi-solids). XFMS canuncover structural waters,cavities, validate antibody-antigen complexes, andcomplement structure-functionstudies19, 27-29. XFMS detects acovalent modification of theresiduethroughradiolysis(Figure5). Unlike hydrogen-deuterium(HD) exchangewhere side-chainexchange rates are too fast fordetection,solventaccessibilityofresidues by XFMS will not go

undetected.XFMSisaproductivetechniquewithanotablepublicationdetailingdisorderedcompactstateoftheestrogenreceptortransactivationdomain30,GPCRreceptorG-proteincomplexassembly31andmostrecently,validationofnanobody-COVIDspikeproteincomplexeswhencryo-EMandMXfailed32.

BioSAXShas been an enormously successful companion toMX33.However, bioSAXS interpretations arenotoriouslyambiguousastheexpertisetoperformrequisitemoleculardynamicscomputationsstillremainsinthedomainofexperts.XFMSandDXTofferrapid,complementarytechniquesthatcanresolvemodellingambiguitiesandbeextendedtostructuralstudiesofproteinswith intrinsicallydisordereddomains.Thestructure-functionparadigmguidesourinterpretationofhigh-resolutionstructures,however,thepictureis incomplete without knowledge of the underlying dynamics required for function. All biologicalmacromolecular machines move and once we observe this happening the inter-relationships andmechanismofactionbecomeobvious.

Figure5 Hydroxyradical footprintingofHepatitis Bvirus genomicRNAusingXFMSfrom NSLS-II. For nucleic acids, sites of modification leads to polynucleotide chainbreaksinastructure/dynamics-dependentfashion.Themodificationpropensitycanbedetermined in high-throughput modes via capillary electrophoresis or NextGensequencing.Thelatterisusefulwithlargegenomes,e.g.Covid-19whichis~30kblong.A)CartoonofviralRNAgenome.B) Footprintingresiduereactivities fornakedRNA(green) and reassembled nucleocapsid-like particle, NCP (blue), error bars fromtriplicate samples. Reassembly is acutely sensitive to the PS1 RNA region, XFMSexperiments reveal nearly complete protectionof PS1 inNCP.C)M-fold secondarystructurepredictions incorporating theXFMSresults.DatakindlyprovidedbyPeterStockley (AsburyCentre,Univ.Leeds),ReidunTwarock (Univ.York)andNikeshPatel(AstburyCentre,Univ.Leeds).

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3.3 Diamond-IIportfolio

The original 2004 SAXSRoadmapforDiamondbyDr.TimWessandDr.NickTerrill was forward-thinking and prophetic inits recommendation thatthe UK SCM communityrequiredthreespecializedSAXS beamlines. OurproposalforX4SCMbuildsonthisroadmap(Figure6)whilstintroducingthetwonew X-ray techniques forstudying soft matterproblems. X4SCMoptimally exploits theemittance properties ofthe X-ray source inDiamond-II as the lowdivergence aids inproducing a nearlyparallel, monochromaticbeam for USAXSmeasurements.Currently,themostaccurateangularresolution in the USAXSregime isachievedwithaBonse-Hart camera11 butis limited by significantly

increasedexposuretimesandbackgroundscattering,andintrinsicallyblocksaccesstoconcurrentSAXSandWAXSobservations.Furthermore,theSCMcommunitydoesnothaveageneralpurposesynchrotronX-raysourcefornon-scatteringtechniques.

SCMmaterialseitherinthesolid,liquidorglassystatesarecomposedofnano-structuredbuildingblocksthatdeformundermoderatethermalfluctuationsormechanicalstresses.Ascompositionofmaterialscanbevaried,thereareseveralquestionsthatmustbeinvestigatedtounderstandanemergentpropertysuchaswhat are the size and shape of structural features present in thematerial? How are these featuresspatiallyarrangedorcorrelated?Anddothesefeaturesrelatetoadesiredmechanical,electronic,interfacialorbiomedicalproperty?Havingacomplete,reciprocalspacepicturefromthemoleculartomicron-scaleprovidesthenecessaryinformationtoaddressthesequestions.Thisobservationwindowiscriticaltofuturematerial engineering. USAXS is a specialized measurement using either a Bonse-Hart camera or anextremely long camera length forcing the investigator to choose either USAXS or SAXS during ameasurement,neverboth.Bonse-HartrequiresextendedmeasurementtimesduetotheneedtoscancomponentswhereasUSAXSwithalongcameraoncurrentsourcesalsohasmuchlongermeasurementtimes. Therefore, X4SCMwill be transformative in allowing for simultaneousUSAXS-to-WAXS during asingleexposure.Giventheexpectedphotonfluxofthebeamline(>1013photonspersec-1),time-resolvedstudies of soft matter systems with X4SCM will offer a step-change in measurement efficiency asUSAXS/SAXS/WAXSmeasurementsarenolongerdecoupled(Figure9).

Figure 6 Timeline of SAXS development at Diamond and future vision SCM X-rayinstrumentationenabledbyDiamondII.

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DXTandXFMSarehighphotonflux,polychromaticX-raytechniques.ForDXT,backgroundscatterisdirectlyproportionaltobeamsize.ExperimentsatB16,whilepositive,werechallengingduetothelarge300-micronbeamandwewouldseekanopticalsetuptofocusthebeamtosub-microndimensions.Inthiscase,photonflux is sacrificed forbeamsize albeit deliveringnearly 1013 photons・ sec-1. ForXFMS,beamsize is notcritical,andalarge,unfocusedbeamdirectlyfromtheundulatorwouldbesufficientforexperimentsasthebeamdivergence fromanHPMU inDiamond-IIwill beminimal. TogetherwithbioSAXS, XFMSandDXTrepresent a full complement of solution-state biophysical techniques for structural biology. MostsynchrotronswithastrongMXusercommunityoffersolution-stateSAXSasacomplementarytechniqueand thiswill be true in4th-generation facilities,however,no facilityoffers all threeasadedicateduserprogram.

3.4 Academicusercommunityandbeneficiaries

The UK has world leading academic expertise in everyaspect of soft-matter science ranging frompolymer andsurfactant synthesis, manufacturing and end-of-life(environmental waste) management to biologicallyinspired materials and nano-healthcare. Between 2014and 2020, UK scientists studying polymers, proteins,detergents,surfactants,gels,bone,cartilage,colloids,andlipidscontributedto20,974publicationsaveraging4,195publications per year. TheUK SCM community is large,robustandproductive.TheintersectionofsmallangleX-ray scattering with this community has produced 153publicationsperyear(2014-2020,6-yearaverage).Overthis same period, I22 has been more than 2-timesoversubscribed(Figure7).Thisoversubscriptionwasnotalleviated by the introduction of the phase III B21beamlineindicatingthatB21caterstoanon-overlappingSAXS user community. In fact, during the last threeAllocationPeriods,theI22oversubscriptionrateincreasedeven while B21 delivered its highest number of visitssuggesting growing demand. In 2020, B21 and I22delivered122peer-reviewedpapersconstituting79.9%ofSCM-SAXSoutputintheUK.ThedatastronglysuggestthatDiamondisamajordriverofSCMX-rayscienceandthatthe addition of the X4SCM beamline addresses majorneedsinaccessibilityandexperimentalcapabilities.

Furthermore,B21nowprovides>240usersessionsperyear.Thisscientificcommunityhadbeenlargelyunservedandundeveloped in theUKuntil2014whenB21becameanoperationalbeamline.Prior to2014,theUKbioSAXScommunitywassmallwhereexperimentsweremainlyperformedatSOLEIL,ESRFand PETRA. The introduction of B21 beamline at Diamond encouraged growth of the UK bioSAXScommunitythroughlinkageswiththeMXcommunity,MembraneProteinLaboratoryandvariousdoctoraltrainingprograms.B21nowcontributestoover84papersperyear.TheimpactofB21waslargelyrealizedthroughrelentlessoptimizationofmeasurementsonliquidsamples.

Figure 7 A) Historical oversubscription levels for I22since2007.Rateaverages2.8andreachesapeakof6.B)Highlyroteexperimentsenablehighautomationasachieved on MX beamlines; delivering 300 to 400sessions per year. In contrast, SCMexperimentswithsignificantset-uptimesgreatly limitaccessibility (baseon2019).

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Addition of X4SCM increases user access to aUSAXS/SAXS/WAXSinstrumentwhilstintroducingtwonewsynchrotron techniques (XFMS and DXT) to the UK SCMcommunity. The NSLS-II (Brookhaven, NY, USA) and ALS(Berkeley, CA USA) both offer dedicated beamlines forXFMS.Demandforfootprintingmethodsisgrowing(Figure8) and more importantly, the UK already has a growingoxidative footprinting community at the Astbury Centre(Univ.ofLeeds)thatusesbothlasersandtheNSLS-IIfacility.Dr. Peter Stockley (Astbury Centre) used XFMS to followassemblyofvirusparticlesandRNApackinginvivo.WewillworkwithAstburyCentre,namelyDr.FrankSobott(ChairofBiomolecular Mass Spectrometry), to help establish thisburgeoningcommunity.

SinceDXTandXFMSwillbenewtechniquesatDiamond,wewillbuildauserprogramthroughlinkageswiththebioSAXS,MX,MembraneProteinLaboratoryandeBICcommunities.InterpretingbioSAXSexperimentsoftenrequiresintensivecomputationalapproacheswheredomain flexibility, dynamics or conformational changes are inferred. These are hypotheses that can beuniquelytestedbyDXTandXFMS.OurinitialuserprogramwillstartbyidentifyingbioSAXSexperimentsthatcouldreadilybenefitfromaDXTorXFMSinvestigation.WehavealreadytrialledaDXTexperimentonB16withDr.LucaPellegrini(Cambridge)studyingeffectsofmutationsonazinc-fingerwithinacoil-coiledproteininvolvedinmeiosis.BioSAXSexperimentssuggestedstiffeningoftheproteinwithlossofthezinc-finger which was subsequently validated using the time-resolved DXT measurements. We envisage aDXT/XFMSuserprogramthatwouldutilize~10%(20days)oftheX4SCMbeamtime.Thiswouldsupport~20different user groups per year. In preparation forHIERARCHY,wewill developUSAXS expertise bybuildingaBonse-HartcameraonI22.WehaveidentifiedseveralI22users(seeAppendix)thatwouldbenefitfrom USAXS measurements. However, Bonse-Hart measurements require significant time and greatlyconstrainsampleenvironments.Nevertheless,collectingUSAXSinformationforselectexperimentswillaidus developing software and modelling expertise for Diamond-II. We anticipate that HIERARCHY couldsupport40to50usergroupsperyear,similartoI22’suserprogramtoday.

3.5 Industrialusercommunityandbeneficiaries-impactonUKPLC

The ability to drive down cost-per-sample per measurement will have profound effects on industry.Consider that a comparable USANSmeasurementmay take 6 to 8 hours (nearly £10,000) per sample.HIERARCHYcanachievethesamemeasurementin1secondor360samplesperhour,providing~20,000-timesdecrease in cost-per-samplewhileobserving themolecular tomicron length-scales.Drivingdowncost-per-sampledrivesdownriskandthisencouragescompaniestoengageinmorespeculativeresearchendeavoursfordiscoveryratherthanresearchforincrementalprogress.MitigatingriskexposurethroughmeasurementefficiencieswillfundamentallydriveindustrialengagementatDiamond.

The formulatedproducts industrydevelopsSCMmaterials to solve industrial, consumerandhealthcarechallenges. There has been a recent explosion in reductionist, molecular engineering approaches todeveloping these active products. This approach has been strongly supported by the UKs cross-sectorsuccessandexpertiseinSCMresearch.SCMformulatedproductsarecriticaltomanyindustrieshighlightedby the timelyexamplesof the firstCOVIDvaccinesbyPfizer andModernawhichusedengineered lipidnanoparticlecapsulesasRNAdeliveryvehicles34-35.

Figure 8 Graph showing annual growth inoxidative footprinting publications (PubMedsearch).Producing35to40papersperyear.

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The primary goal of industrial SAXS users has been to use structural analysis as a product engineeringfeedback parameter.While current SAXS/WAXS capability provide valuable insights into the functionaldesign and activity of formulated products, the inaccessible micron length scale is a missing designparameter for engineeringproduct stability: anareawheredevelopmenthas thepotential tounderpinenormousenvironmentalandcostefficiencyimprovements.SimultaneousUSAXS-to-WAXSmeasurementacross5ormoreordersofmagnitudeinscatteringangles(Q-range)isvitaltoawiderangeofindustrialapplicationsacrossarangeofsectors.ThecurrentinstrumentsatDiamondareexcellentformicellar-typestructures.However,manyformulatedproductsarecomprisedofmultipleingredients/chemistrieswhicharepresentacrossmultiplelengthscales(touppermicron-sized).Forexample,Infineumformulateengineoilsasmixturesofsurfactantsandpolymers(whichformmicellesandalsolargersystems).Thestructureanddynamicsofsuchsystemscurrentlycannotbefullycharacterisedinasingleexperiment.Theabilitytosimultaneously study structure across several decades in Qwould be extremely valuable and confer acompetitiveadvantage.Inaddition,insomesystems,crystallisationcanoccurwhichmaybeadvantageous,forotherscrystallizationmustbeavoided,sohavingtheabilitytoperformWAXSsimultaneouslywithUSAXSwouldbereallyapowerfultool(Prof.PeteDowding).

There is also enormous industrial potential and interest in the proposed non-scattering techniques.Hydrogen-deuterium exchange (HDX) mass spectrometry is a commonly applied technique in thepharmaceutical industry36. XFMS will be a competing technique to HDX with notable differences. HDXprobesbackboneamidesofproteinsthroughnon-covalentlabellingoftheprotons.Thelabelwillhavealimited lifetime and contributes to decay in the signal. XFMS is a covalent modification that probesfunctionalgroupofresidues,ismoresensitiveandcanprobefastertimescales.WebelieveXFMSwillbeattractivetoindustryforprobingantibody-antigeninteractions,validatingconformationalchangesandinvivoexperiments.XFMScanalsobeusedtoprobepolymer/surfactantinteractionsbutthisareawillrequirein-house research support to develop themethodology. DXTwill be a very novel technique to the UKcommunity.DXT’sabilitytoprobedynamicshasapplications inpolymerdynamicsandhasalreadybeenappliedtoostudyingdynamicsinsyntheticrubberformulations(personalcommunication,Prof.Sasaki).

3.6 Comparisontoothersynchrotronfacilities,currentandplanned

ID02(ESRF,Grenoble,FR),theAPSUSAXSfacility(APS,Illinois,USA),andBL03XU(Spring-8,JP)currentlyprovide USAXS measurements for SCM investigations. The APS facility can provide USAXS/SAXS/WAXSmeasurementswithin5minutes, but themeasurement across theentire scattering vector range is notsimultaneous.ID02offersa31-metercameralengthwithaminimumbeamsizeof20microns-squared(8.0–20.0keV).TheUSAXS/SAXS/WAXSrangeisachievedbyavariablecameralengthwiththedetectors invacuum.Again, theentirepossiblerangeof lengthscales isnotmadefromasinglemeasurementbutaseriesofmeasurementsatspecifiedcamera lengths. ID02 isthemostcompetitive instrumentwithinEUthatwillbeassociatedwitha4thgenerationsynchrotron.

OurX4SCMproposalisdesignedtoallowouroriginalSAXS/WAXSbeamlineI22toreachitsfullpotentialinDiamondIIandstrengthenthecapabilitiesoftheSCMgroup.I22hasexceptionalmicro-focusingcapabilitiesand is ideal for tomography,GISAXS andmapping experiments.However, I22 is our only SCMgeneral-purposeSAXSbeamlinewhichmakesbeamtimehighlycompetitivewhilstcateringtoadiversearrayofexperimentalsetups.Thecostofmaintainingsuchasgeneral-purposeinstrumentismanifestedinefficiency(usersessionsperyear),competitivenessandanunder-servedcommunity.It isclearfromrecentUSAXSstudiesonchocolates,epoxies,additivemanufacturing,aerogels,porouscatalystparticles,fibrillarrheologymodifiersandPickeringemulsions(e.g.skincreamtomayonnaise),thatUSAXSremovesalluncertaintyinthehierarchicalstructurebyprovidingacompletereciprocalspacepicture.X4SCMwillallowustomigrateacoresetofexperimentsfromI22thatshouldhavealwaysincludedUSAXSinformation.Furthermore,by

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providingroutineUSAXStoWAXSmeasurements,X4SCMwill initiateanewera inSCMX-rayscatteringstudiesbysettingthegoldstandardinpeer-reviewedSCMpublications.

Specializationpromotesautomationandefficiency.ForB21,automationofliquidsamplesdelivers~240uservisitsperyeartranslatinginto>80peer-reviewedpublicationsin2020.Similarly,AdvancedLightSource(Berkeley, CA) beamline 7.3.3 specializes in polymer thin-films provides high-throughput automation ofGISAXSyielding~170papersin2019.Asageneralpurposebeamline,I22isatitsmaximumuserthroughputandwithoutX4SCM,I22willnotrealizeitsfullpotentialasaspecializedmicrofocusSAXSinstrument.Suchspecializationwillnotonlyincreaseusersessioncapacity(throughselectautomation)butalsoallowI22tocontinuetodevelopcompetitivetechniquessuchasSAXStensortomography3,37.

Most synchrotrons with a strong MX user community offer solution-state SAXS as a complementarytechniqueand thiswillbe true in4th-generation facilities,however,no facilityoffersall three (bioSAXS,XFMS and DXT) through a dedicated user program. 17-BM at the NSLS-II is the only dedicated XFMSbeamlineintheworldprovidingfocused,5-16keVpinkbeam.Beamline3.2.1(ALS,Berkeley,CA)isunder-developmentasadedicatedXFMSsource.Finally,DXTisnotofferedasauserprogramatanyfacilitywhichgives Diamond a unique, competitive opportunity. An offering of all three solution-state techniquesdecouplesstructuralbiologyfromthepurviewofMXorcryo-EMallowingformoreengagingscience.

Finally,themostsevereconsequenceofnotbuildingX4SCMwillseetheSCMgroupandDiamondnolongerbeworld-leading inthisspace. It isbecomingincreasinglyclearthatUSAXSshouldbeprovidedformostSAXS investigations of SCM problems and Diamond will not meet this demand if USAXS remains as adisparatetechnique.Furthermore,ashifttomicro-focusSAXSonI22willcompeteoutothersectorsofourexistingusercommunityandGISAXSwillnotbeafullyrealizedexperimentalmodalityatDiamondleavingP03(Petra-III)astheleadingfacilitywithintheEU-UK.

3.7 CombinedimpactofprojectandaddedvalueinrelationtoactivitiesontheHarwellCampusandbeyond.

TheHIERACRHYmodalityofX4SCM linksnaturallywith ISIS (HarwellCampus)asdoes I22andB21. ISISalreadyprovidesSANSandSESANSmeasurementsandHIERARCHYwouldbeacomplementaryinstrument.WeperceivenewopportunitiescouldbeestablishedwiththeFarardayInstituteasUSAXS-to-WAXSisusedto investigate porosity and microstructure changes in electrodes during charge-discharge cycles andstructuringinpolymerelectrolytesduringuse.BatteryresearchiscriticaltotheUKandHIERARCHYcouldcertainly play an active role in helping the UK achieve improved batteries for an electric car future.Furthermore, our proposed instrumentation portfolio is key to achieving the goals of the Henry RoyceInstituteofAdvancedMaterials,specificallytheBraggCentreforMaterialResearchwhoseresearchthemesinmultiscalematerials,bionanotechnologyandsoftmatterbenefitfromtheDiamondSCMecosystem.

TheRosalindFranklin Institute (HarwellCampus)promotes twosciencethemes,namelyBiologicalMassSpectrometry and Structural Biology, that would benefit from SNAPSHOT. XFMS’s main method fordetectionishigh-resolutionmassspectrometry.Webelievechallengespresentedbyfunctionalproteomics,particularlymappingchemicalinformationinvivocouldbemetwithXFMSaschangesinresiduereactivitycouldbecorrelatedtoexpressionpatternsintissues.Secondly,SNAPSHOTcouldreadilycontributetotheStructuralBiologytheme,particularlyinvalidatingresiduesinvolvedinnanobodybinding.Certainly,atpoorcryo-EM resolutions, additional information may be required to validate orientation of the nanobody.SimilarworkwasperformedusingXFMSandnanobodybindingtotheCOVID-19spikeprotein32.

HIERARCHYwillgeneratesignificantamountsofdatathatwillneedonsiteprocessingforreal-timefeedbacktousers.However,weseeasignificantchallengewillbeinproviding3Dmodels.ModellingSAXSdata,evenusingcoarsegrainedtechniques,iscomputationallyintensiveandunderdevelopedforsoftmattersystems(otherthanstructuralbiology).These,additionaldataandscientificchallengesdiscoveredbyX4SCMcanbe

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metthroughrelationshipswiththeAdaLovelaceCenterandSFTCCoSeC.Currently,theAdaLovelaceCenterisprovidingcriticalsupporttodevelopmentsinreflectometryatDiamond,whilsttheCoSeChasrecentlycompletedthebioSAXSprogramsleadbyDr.StevePerkins(UniversityCollegeLondon).Ourcomputationalchallenges will naturally build critical relationships with these organizations for delivering world-classsciencetoourcommunity.

4. BeamlineperformancespecificationandrequirementsComparativeperformancesinX4SCMcanbeappreciatedthroughtheHIERARCHYend-stationwhichismostcomparabletoI22.SNAPSHOTisintroducingtwonewtechniquestoDiamond,onlyDXTwastrialledonB16.

Table:ComparisonofPerformancesbetweenI22todayandHIERARCHYinDiamondII

HIERARCHY I22

Errorangularresolution(q=0.002Å-1) <0.5% ~60%

ExposuretimeforUSAXS 1second 240to300seconds

Fluxatsample(photons·second-1) 1013(50micron2,parallel) 1012(14micron2focused)

Maxcameralength(meters) 38 9.9

SeeFigure9

USAXS on I22 requires the Bonse-Hart camera which means the USAXS measurement is mechanicallyscanned across an angular range. This requires nearly 5 minutes and excludes the SAXS and WAXSinformation.TomeasureSAXSorWAXSinthisconfiguration,theUSAXScameramustberemovedwhichaddsmoretimetothemeasurement.Practically,adedicatedUSAXS/SAXS/WAXScamerawillsave>300%inexposuretimedirectlyfromthelackofscanning.Alargestperformancegainwillbeintheaccuracyofthemeasuredangular resolution (Δq/q) at the lowest scatteringangles.Beamdivergence is the largestcontributortoΔq/q(Figure9B).OnI22,Δq/qis~60%at0.002Å-1whichreducesdowntolessthan0.5%inHIERARCHY.

SNAPSHOT will use a single harmonic from the HPMU providing nearly 1015 photons · second-1 ofpolychromaticX-rays.DXTonB16usedapink-beamina300micron2beam.Althoughtheexperimentwassuccessful,itwasperformedwithanexceptionallyhighbackground.Scatteringfromeachofthegoldnano-crystals is swamped by the background scatter of the surrounding air, solvent and support material(Kapton).Scatterfromsolventandsupportmaterialisdirectlyproportionaltothecross-sectionalareaoftheincidentbeam.AproperlydesignedsampleholderwillminimizetheairgapbetweentheincidentbeamandsampleakintoVMXm.

4.1 Additionaldevelopmentsrequired

HIERARCHY data processing will be an extension of the world-class analysis performed on I22. TheSAXS/WAXSteamledbyDr.TimSnowhasprovidedahighlevelofautomationwhichenablesreal-timedataprocessingandanalysisincorporatingdatafromalldetectorstooutputseamlesslyacrossthefullrangeoflengthscalesmeasured.ThiswillbereadilyextendedtoHIERARCHY.

ThemorechallengingworkflowsresideinDXTandXFMS.SinceDXTisasetofimageframeswithdiffractionspots,wewilladaptDAWN(in-housesoftwarethatisthebackboneofI22’sdataprocessingpipeline),toautomate diffraction spot identification and tracking. The sample environment for DXT is under

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development andwill be ready prior to completion of Diamond-II. For XFMS,wewill be adopting andcollaboratingAstburyCentreandwiththeAdvancedLightSourcesXFMSgrouptoprovideautomationinmassspectrometrydataanalysis.AtDiamond,asuccessfuluserprogrammustincludeprovidinguserswiththe reaction rate curves for allmapped residues in the target proteins.Wewill invest in post-doctoralresearchassociatesandstudentshipsstartingin2021tobeginXFMSatDiamondviaB16.

5. Schematicoutlineofbeamlineorproject

5.1 Source

X4SCMshouldprovidethehighestpossiblepolychromaticfluxforDXTandcoverasuitablerangeof5to30keVforXFMS.TheX4SCMbeamlinerequiresahybridpermanentmagnetundulator(HPMU).Wehaveidentifiedmid-straightK13thatwouldsupporta1.5-meterHPMUandgivethenecessaryspacefora38+metercameralength.

Figure9A)BeamlinelayoutforXFMSatK13(kindlyprovidedbyMartinBurt).SNAPSHOTwillexistonthefirstbreadboardtablefollowedbyHIERARCHY’stable.Beamcollimatingopticsarewithinthestorageringbeforethefront-end shutter. Beamline extends all the way to the outer wall of synchrotron tomaximize distance. B)Contributionstoscatteringangleresolution,withinUSAXS,dominantsourcesoferrorwillbeduetobeamheightandpixelbinning.Parallelqualitiesofthebeam(divergence)arenolongerdominatingcontributions.Normally,Δq/q>100%inthelowestscatteringangles.C)XFMSend-stationatAdvancedLightSource(kindlyprovidedbyCorieRalston).Allcomponentsfitwellwithin1-squaremeter.YellowarrowindicatesdirectionofX-rays.DXTrequiresasimilarfootprintalbeitwithoutthedetector.

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5.2 Optics

Thebeamlinewillrequiremultiplefocusingopticsduetothedualmodalities.Toprovidethemostparallel,collimatedbeam,wedesireawhite-beammirror,CRLorequivalentopticupstreamofthemonochromator,preferably locatedwithin the storage ring (Figure 9). The location of the upstream collimating optic isnecessarytomaximizecollimationofthebeamsuchthattheincidentbeamisasparallel(lowestdivergence)aspossibleasthebeamtravelstheentiredistanceofthebeamline.Oursimulationsshowthattheerrorinangularresolution(Δq/q)willbe~30%withbeamdimensionsof~50x50microns(FWHM)atthedetectorposition(Figure9).Followingthecollimatingopticandinsidetheopticshutchwillbeacombinationdoublecrystalmonochromator(DCM)formonochromaticlightandamulti-layercrystalforpinkbeam(highflux,polychromatic light).Nextwill beoptics forDXT (setofKBmirrors) for focusing thebeamdown to<1micron.XFMSwilltakethedirectbeamfromthemonochromatoranddoesnotrequireadditionaloptics.Stabilityisessentialwherewewillrequirenano-positioningto10nm.Beamstabilityatthislevelofprecisionisessentialwherethetemperatureenvironmentofbothstorageringandbeamlineneedstoat leastasgoodas±0.1.

5.3 End-station(s)

HIERARCHYandSNAPSHOTwillhaveseparatebreadboardtablesdedicatedforeachmodality.HIERARCHYwillbebasedonI22’sconfiguration.WewouldlikedataacquisitiontobemostsimilarbetweenI22,B21andHIERARCHYsuchthatourvisitorshaveacommonuserexperience.

HIERARCHY requires four sets of detectors strategically placed to provide seamless USAXS/SAXS/WAXSmeasurements(Figure9A).ThedetectorsforHIERARCHYconsistoftwoWAXS(Pilatus2Morequivalent),MAXS(Eiger9M),SAXS(Eiger9M)andUSAXS(Eiger9M)detectors.Thesedetectorswilloperateinavacuumataframerate>500Hz.

SNAPSHOTwillutilizea4MTRISTANdetectorforDXTmeasurementsandamassspectrometerforXFMSexperiments. The instrumentation footprint for DXT or XFMS is small (Figure 9C) and we envisage aswappabletabletopconfiguredwitheitherDXTorXFMScomponents.XFMSusesasetofsyringepumps,fast shutter, laser (for excitationofAlexaFlour dye), camera andmicrofuge tube carouselwhereasDXTrequiresanXYstage,Tristandetector,photo-diodeandbespokein-boardnoseconeforholdingthesamplearray.

5.4 Samplepreparationfacilities

Sample preparation will use SCM current labs, 11 (biology), 12 (chemistry) and 14 (chemistryinstrumentation).DXTrequiresavacuumovenforchemicalvapourdepositioninthesynthesisofgoldnano-crystalsandahighfrequencysonicatorforformingsuspensions(preparesnanoparticles).ForXFMS,themassspectrometerwouldbelocatedinlab14andproteolyticdigestionofsampleswilloccurinlab12.Anycellularinvivosamplepreparationwilloccurinlab11.HIERARCHYuserswilluselabs11and12.

5.5 Computinginfrastructureandsupport

Demandforcomputingresourceswillbehigh.HIERARCHYrequires4Eiger9Mequivalents.Atfull-framerate, thedatanetworkwillneed to transferat620gigabitper secondsusingdisk storageat62GBpersecond.Full-framemeasurementswillbenecessaryfortime-resolvedstudies.DataprocessingwillutilizetheexistingpipelinesbeingdevelopedonI22butwillneedtobeexpandedtohandlethelargerdatasets.

DXT is another extreme data intensive measurement. The Tristan 4M detector would generate 480terabytesina2-hourperiodassuming50pointsper10x10mmsampleand4samplesperhourina24-hour

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period.SinceDXTislikelytobe10daysperyear,wecanestimate~2000terabytesofdatastoragefortheuserprogram(assuming1-dayforsetupandoptimization).WewillrequirenewdevelopmentsinDAWNtoprocess the diffraction spots. For a DXTmovie, diffracted spots will need to be identified and tracked(decomposedintothetaandchivalues).TheanalysiscanbefullyautomatedandwillbuildupontheworkbyDr.YujiSasaki.OurplanistodevelopthesoftwaretoolswithinDAWNaswepilotaprogramonB16.

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Gupta,S.;Barsi-Rhyne,B.;Belyy,V.;Barile-Hill,A.W.;Nock,S.;Liu,Y.;Krogan,N.J.;Ralston,C.Y.;Swaney,D.L.;Garcia-Sastre,A.;Ott,M.;Vignuzzi,M.;Consortium,Q.S.B.;Walter,P.;Manglik,A.,AnultrapotentsyntheticnanobodyneutralizesSARS-CoV-2bystabilizinginactiveSpike.Science2020.33. Brosey,C.A.;Tainer,J.A.,EvolvingSAXSversatility:solutionX-rayscatteringformacromoleculararchitecture,functionallandscapes,andintegrativestructuralbiology.CurrOpinStructBiol2019,58,197-213.34. Pardi,N.;Hogan,M.J.;Porter,F.W.;Weissman,D.,mRNAvaccines-anewerainvaccinology.NatRevDrugDiscov2018,17(4),261-279.35. Jackson, L. A.; Anderson, E. J.; Rouphael, N. G.; Roberts, P. C.; Makhene, M.; Coler, R. N.;McCullough,M.P.;Chappell,J.D.;Denison,M.R.;Stevens,L.J.;Pruijssers,A.J.;McDermott,A.;Flach,B.;Doria-Rose,N.A.;Corbett,K.S.;Morabito,K.M.;O'Dell,S.;Schmidt,S.D.;Swanson,P.A.,2nd;Padilla,M.;Mascola,J.R.;Neuzil,K.M.;Bennett,H.;Sun,W.;Peters,E.;Makowski,M.;Albert,J.;Cross,K.;Buchanan,W.;Pikaart-Tautges,R.;Ledgerwood,J.E.;Graham,B.S.;Beigel,J.H.;m,R.N.A.S.G.,AnmRNAVaccineagainstSARS-CoV-2-PreliminaryReport.NEnglJMed2020,383(20),1920-1931.36. Masson, G. R.; Jenkins,M. L.; Burke, J. E., An overview of hydrogen deuterium exchangemassspectrometry(HDX-MS)indrugdiscovery.ExpertOpinDrugDiscov2017,12(10),981-994.37. Schroer, C. G.; Kuhlmann, M.; Roth, S. V.; Gehrke, R.; Stribeck, N.; Almendarez-Camarillo, A.;Lengeler, B., Mapping the local nanostructure inside a specimen by tomographic small-angle x-rayscattering.AppliedPhysicsLetters2006,88(16).

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7. AppendixI

Table: PutativeHIERARCHYUsers

PrincipalInvestigator Institution ScienceArea

KellyS. RossUniversity Biomaterials

AbelR. ImperialCollegeLondon Biomaterials

BrunelloE. King'sCollegeLondon Biomaterials

DeméB. InstitutLaue-Langevin Biomaterials

GuptaH. QMUL Biomaterials

LiebiM. CharmersInstituteTechnology Biomaterials

PerimannA. UniversityofBristol Biomaterials

TingV. UniversityofBristol Biomaterials

MembraneBiophysicsGroup(N.Brooks,O.Ces,J.Seddon,R.Law,R.

Templer,LDiMichele,Y,Elani)ImperialCollegeLondon BiomaterialsandFormulated

Products

WynneK. UniversityofGlasgow Chemistry

BriscoeW. UniversityofBristol Colloids

EdlerKJ. UniversityofBath Colloids

JacksonA. ESS Colloids

McGillivrayD. UniversityofAuckland Colloids

SeddonA. UniversityofBristol Colloids

SquiresA. UniversityofBath Colloids

TylerA. UniversityofLeeds Colloids

DunbarADF. UniversityofSheffield Energy

HintermairU. UniversityofBath Energy

LidzeyD. Sheffield Energy

CharpentierVJ. UniversityofLeeds EngineeringMaterials

BenningL. GFZPotsdam Environment

BrookerR. UniversityofBristol Environment

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PfrangC. UniversityofBirmingham Environment

StawskiT.BAMFederalInstituteforMaterialsResearchandTesting Environment

RodriguezBlancoJD. TrinityCollegeDublin Environment

RappoltM. UniversityofLeeds FoodScience

EmmerlingFL.BAMFederalInstituteforMaterialsResearchandTesting InorganicMaterials

Fernandez-MartinezA. InstitutdesSciencesdelaTerre(ISTerre) InorganicMaterials

MurrayC. DiamondLightSource InorganicMaterials

SankarG. UniversityCollegeLondon(UCL) InorganicMaterials

SchneppZ. UniversityofBirmingham InorganicMaterials

SmithA. DiamondLightSource InorganicMaterials

SvardM. KTHRoyalInstituteofTechnology InorganicMaterials

GagliardiS. Heriot-Watt Materials

HollambyMJ. KeeleUniversity Materials

MeldrumFC. UniversityofLeeds Materials

RobsonJ. UniversityofManchester Metals

BennettT. CambridgeUniveristy MOFs

Fairen-JimenezD. CambridgeUniveristy MOFs

ChevallardC. CEASaclay Nanomaterials

PauwB.BAMFederalInstituteforMaterialsResearchandTesting Nanoparticles

ArmesS. UniversityofSheffield Polymers

DerryMJ. AstonUniversity Polymers

GoughT. BradfordUniversity Polymers

HallettJ. ImperialCollegeLondon Polymers

HeeleyE. OpenUniversity Polymers

HughesD. WarwickUniversity Polymers

MykhaylykOOM. UniversityofSheffield Polymers

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SchillerT. WarwickUniversity Polymers

TophamP. AstonUniversity Polymers

WarrenN. UniversityofLeeds Polymers

Company SubjectArea

9 industrial users have been identifiedthatwouldbelikelyusersofHIERARCHY.Namescannotbedisclosed.

Pharmaceuticals, foodprocessing,fuel additives and lubricants,customercare

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8. Expressionsofinterest&supportfromthecommunity(1pagemax)

Statements of support summary Total number of submissions: 153

Type of organisation supporting Percentage of respondents Academic 88.2% Government 7.2% Industry 3.9% Non-Governmental Organisation (NGO)

0.7%

Diamonduserstatus Percentageofrespondents

NotcurrentlyauseratDiamond 14.4%

CurrentlyauseratDiamond 85.6% Excluding Diamond staff, 158 individuals contributed 154 statements of support (including attached letter). Our support community is diverse with a strong showing from life, material and chemical sciences. Although direct industry support contributed ~4% of the total, SCM science is translational with many of our users working with or funded by industrial partners. Furthermore, many supporters highlighted X4SCM will broaden the user community by providing new techniques for investigating dynamics. Through these statements, our supporters show that X4SCM can meet challenges across a broad range of applications including drug delivery for treating cancer, improving photovoltaics for sustainable energy, antimicrobials, polymer self-assembly and nano-particle synthesis. Letters of support provided for our Wellcome Trust Diamond-II application expressed support for SAXS in drug discovery, and the step-change in sample throughput enabled by the upgrade. These letters include support from The Rosalind Franklin Institute and five structural biologists from London School of Hygiene, Birbeck at the University of London, Wellcome Center for Human Genetics (Univ. Oxford) and University of Warwick.

KeyforstatementsinAppendixA Respondent'sprimaryfieldofresearch Percentageofrespondents Life Sciences & Biotech 43.1% Materials Sciences 22.2% Chemistry 20.3% Engineering & Technology 5.2% Physics 4.6% Earth Sciences & Environment 2.6% Energy 2.0%

Respondentlocation PercentageofrespondentsUK 64.1%International 35.9%

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Engagement webinar summary Date of webinar: Friday 23rd October 2020 Number of attendees: 92 Attendeelocation PercentageofattendeesUK 63%International 37%

X-rays for Soft- Condensed Matter (X4SCM)

Documents

Transcript of X-rays for Soft- Condensed Matter (X4SCM)