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In order to carry out their functions, proteins need to move. Scientistsatthe IBSGrenobleandEPFL,incollaborationwithENSLyon,havedevelopeda newapproachtothestudyproteinmotionswithunprecedentedaccuracy. Byfreezingproteinsdowntoverylowtemperatures,researchersslowly heatuptheproteinandwatchthedifferentcomponentsoftheproteinas theycombinetoproducethedynamicsthatareessentialforfunction. Proteinsarecomplexmachinesthatareinconstantmotion,movingcontinuously inordertocarryouttheirfunctions.Theirmultiplecomponentatomsalsohave theirindividualmotionpatterns,makingtheentireproteinasystemofnon‐stop highlycomplexmovement.Understandinghowaproteinmovesisthekeyto developingdrugsthatcanefficientlyinteractwithit.Butbecauseofits complexity,proteinmotionhasbeennotoriouslydifficulttostudy.Scientistsat IBS‐Grenoble,EPFLandENS‐Lyon,havedevelopedanewmethodforstudying proteinmotionbyfirstfreezingproteinsandthenslowly“wakingthemup”with increasingtemperature.ThebreakthroughmethodispublishedinScience. Proteinmotionishighlycomplex Motionispartofaprotein’sfunction,allowingittoadjustits3Dshapeand interactwithothermoleculeslikebiologicalmoleculesandsyntheticdrugs. These“functional”motionshoweverarecomplex,andcanbethoughtasthe mechanismofawatch,wheremotionsbetweeninterlockingcogsandsprings,at differenttimescales,resultinthesmoothmovementofthehands. Inaproteinthecogsandspringsarethemoleculesthatmakeitup:aminoacids formitsbackboneeachwithside‐chainsofdifferentmoleculesbranchingouton allsidesinthreedimensions.Inaddition,watermoleculesboundtotheprotein aswellasinthesolutionwhereitexists,e.g.thecell’scytoplasm,addevenmore layersofmotionaldetailtothesystem.Proteinmotionseemsalmostchaoticin itscomplexity,butsomehowcombinestoprovidethebiologicalfunction essentialforlife. Freeze,sleep,wakeup,andmove TheteamofscientistsledbyMartinBlackledgeandLyndonEmsleyhave developedaninnovativesolutiontothemotionproblem:freezetheproteinsand thenwatchthem“wakeup”fromdeepsleep.Proteinmotiondependsonenergy, andtemperatureallowstheresearcherstodialmoreenergyintothesystemina controlledway.Byfreezingproteinsdowntotemperaturesbetween‐168°Cto 7°C,theywereabletoalmostcompletelystopallmotion,thenslowlyraisethe temperaturetothepointwheretheproteincouldregaintheirnaturalmotions, measuringthedynamicsoftheproteinalongtheway.Thisway,itwaspossible tolookateachmotionaproteinexperiencesindividuallyand–moreimportantly –intherightorder. Inordertodetecttheindividualmotionsofproteins,thescientistsuseda spectroscopictechniquecallednuclearmagneticresonance(NMR),which exploitsthemagneticpropertiesofcertainatomslikehydrogen,nitrogenand carbon.Becausetheproteinsinthisstudyneededtobefrozendown,the researchteamhadtoadjusttheirNMRmethodologytoworkwithsamplesat verylowtemperatures,allowingconsistentreadings,andkeepdoingsoasthe temperatureincreasedto“waketheproteinsup”.Tomakelifemoredifficult, samplesthatarefrozensolidaredifficulttoreadinNMR,sointhisstudythe tubecontainingtheproteinshadtoalsobeconstantlyspinningataspecific (“magic”)angletotheNMR’smagneticfield,inordertoimproveresolution. Finally,everyNMRexperimenttookdaystoperform.Thesecomplicationswere overcomebyusinganewlydevelopeddevicethathasbeenspecificallydesigned toworkwithNMRatlowandchangingtemperatures,combinedwithaprecise rotorsystemthatcouldspinthesampleoverlongperiodsoftime. Ahierarchyofmotion Usingtheirinnovativeapproach,theBlackledgeandEmsleyteamsfoundthatthe sequenceofproteinmotionsfollowsaspecifichierarchyastemperature increases:firsttheprotein’ssolutionmolecules,thentheprotein’sside‐chains andwatermolecules,andfinallytheprotein’sbackbone.Thesequence culminatesatafunctionallyactiveproteinattemperaturesevenaslowas‐53°C, wellbelowphysiologicallevels.Thismeansthatthe“wakingup”methodisvery effectiveforstudyingthemotionsofaproteinindividuallyandsequentially, withoutdeviatingfromrealisticconditionsinacell. ThisworkrepresentsacollaborationbetweenIBSGrenobleCEA/CNRS/UJF,EPFL’s LaboratoryofMagneticResonanceandCNRS/ENS‐Lyon. Reference LewandowskiJ.R,HalseME,BlackledgeM,Emsley,L.Directobservationof hierarchicalproteindynamics.ScienceXXXXXX.DOI:XXXXXXXXX