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Springer Theses Recognizing Outstanding Ph.D. Research Steven J. Large Dissipation and Control in Microscopic Nonequilibrium Systems Springer Theses Recognizing Outstanding Ph.D. Research AimsandScope The series “Springer Theses” brings together a selection of the very best Ph.D. theses from around the world and across the physical sciences. Nominated and endorsed by two recognized specialists, each published volume has been selected for its scientific excellence and the high impact of its contents for the pertinent fieldofresearch.Forgreateraccessibilitytonon-specialists,thepublishedversions includeanextendedintroduction,aswellasaforewordbythestudent’ssupervisor explainingthespecialrelevanceoftheworkforthefield.Asawhole,theserieswill provideavaluableresourcebothfornewcomerstotheresearchfieldsdescribed,and for other scientists seeking detailed background information on special questions. Finally,itprovidesanaccrediteddocumentationofthevaluablecontributionsmade bytoday’syoungergenerationofscientists. Thesesmaybenominatedforpublicationinthisseriesbyheadsofdepartment at internationally leading universities or institutes and should fulfill all of the followingcriteria (cid:129) TheymustbewritteningoodEnglish. (cid:129) ThetopicshouldfallwithintheconfinesofChemistry,Physics,EarthSciences, EngineeringandrelatedinterdisciplinaryfieldssuchasMaterials,Nanoscience, ChemicalEngineering,ComplexSystemsandBiophysics. (cid:129) Theworkreportedinthethesismustrepresentasignificantscientificadvance. (cid:129) If the thesis includes previously published material, permission to reproduce this must be gained from the respective copyright holder (a maximum 30% of the thesis should be a verbatim reproduction from the author’s previous publications). (cid:129) They must have been examined and passed during the 12 months prior to nomination. (cid:129) Eachthesisshouldincludeaforewordbythesupervisoroutliningthesignificance ofitscontent. (cid:129) The theses should have a clearly defined structure including an introduction accessibletonewPhDstudentsandscientistsnotexpertintherelevantfield. IndexedbyzbMATH. Moreinformationaboutthisseriesathttp://www.springer.com/series/8790 Steven J. Large Dissipation and Control in Microscopic Nonequilibrium Systems Doctoral Thesis accepted by Simon Fraser University, BC, Canada StevenJ.Large ViewpointInvestmentPartners Calgary,AB,Canada ISSN2190-5053 ISSN2190-5061 (electronic) SpringerTheses ISBN978-3-030-85824-7 ISBN978-3-030-85825-4 (eBook) https://doi.org/10.1007/978-3-030-85825-4 ©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerland AG2021 Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuse ofillustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,and transmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilar ordissimilarmethodologynowknownorhereafterdeveloped. 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ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland –Tothememoryof ThomasGeorgeSmith Supervisor’s Foreword Encompassing several independent research thrusts, Dr. Steven Large’s thesis tackles a wide range of important open questions in nonequilibrium statistical mechanics,asubfieldofphysicsthatpromisesinsightsintothedesignprinciplesof molecular-scale biological systems. Steve’s thesis work establishes a multifaceted extension of the deterministic control framework that has been the workhorse of the field for the past 20 years to systems that are strongly fluctuating and autonomous,therebyfacilitatingtheapplicationofstochasticthermodynamicsideas to understand molecular machines in nanotechnology and in living things. This thesiscontainsseveraldistincttypesofcontributions:purelytheoreticalderivations, numerical simulations to systematically characterize model systems, experimental design,andanalysisofexperimentaldata. In his examination of the control of strongly fluctuating microscopic systems, Steve derived simple, tractable, and surprisingly general conclusions (that upon reflection are intuitive). He subsequently generalized this work to autonomous settings, establishing connections to the chemical kinetics literature. As part of this project, Steve uncovered a conceptual blind spot in recent stochastic ther- modynamics research, establishing the rigorous generalization of fundamental thermodynamicsconceptstoautonomouscomplexsystems. On the applied side, Steve put these theoretical developments to work by designing, analyzing, and interpreting the first experimental demonstration (by collaboratorsSaraTafoyaandCarlosBustamante,UCBerkeley)oftheutilityofthis generallyapplicablemethod(thatsomenaturallyevolvedmachinesshowevidence ofusing)fordesigningenergeticallyefficientcontrolinbiomolecules:driveslowly wherefrictionislargeandrapidlywherefrictionissmall.Heanalyzedrawdatafrom equilibrium single-molecule experiments on small DNA molecules and designed subsequent nonequilibrium experiments demonstrating that protocols optimized using this framework systematically and statistically significantly reduced energy loss compared to naive protocols, across a wide range of experimental unfolding speedsandwildlydifferentDNAmolecules. Taken as a whole, these theoretical advances and experimental demonstrations give a scale on which to evaluate the energetic efficiency of molecular machines, vii viii Supervisor’sForeword guidelines for designing effective synthetic machines, and a perspective on the engineering principles that govern effective microscopic energy transmission far fromequilibrium. Burnaby,Canada Prof.DavidA.Sivak June2021 Acknowledgment Firstandforemost,IwouldliketothankmysupervisorDavidSivakforhissupport and guidance over the past 5 years. You granted me independence to follow my interests and immerse myself in the truest essence of academic research. The experience I have gained by working with you has been essential in strengthening mycapabilities,andhasbeenvitaltomycontinueddevelopmentasascientist. ThroughoutmygraduateeducationIhavehadthegreatopportunityofworking closelywithanumberofcollaborators,fromwhomIhavebenefitedgreatly.Iwould liketothankCarlosBustamante,ShixinLiu,andparticularlySaraTafoyafortheir patienceandperseveranceworkingontheDNAhairpinproject.Iwouldalsoliketo thankRaphaëlChetriteandJannikEhrichfortheircollaborationonvariousprojects throughoutthepastfewyears,Igreatlyenjoyedworkingwithyouboth. I would also like to thank the guidance of my supervisory committee, John Bechhoefer and Eldon Emberly. Your unique approaches to scientific problems and continued feedback through the years has helped to broaden the scope of my thinking. The content of this thesis has been improved and clarified significantly fromyourencouragementandsuggestions. IgreatlyappreciatethefinancialsupportIhavereceivedthroughoutmygraduate studies, including NSERC CGS-M and CGS-D3 fellowships, as well as the Billy Jones and Howard Malm graduate awards in physics, made possible through the continuedgenerosityofSFUdonors. I would also like to thank my parents, Andrew and Sandra, for believing in me through the past 5 years and beyond. Ever since I left to start my undergraduate degree in 2011 at the University of Guelph, I could always depend on your encouragementandunwaveringsupport.IalsowouldliketothankmysisterJenny, herhusbandIan,andsonNate,foralwaysbeingthereforme. Throughtheupsanddownsofgraduateschool,friendsandcolleaguesmakethe worst of times better and the best of times great. I would like to acknowledge the entire cast of Sivak group members over the past 5 years, with a special mention of Aidan Brown and Alexandra Kasper, who helped immensely in the early years of grad school. I also benefited greatly from many colleagues and friends in the broader physics graduate student body, with a particular thanks owing to Chapin ix x Acknowledgment Korosec, Konstantin Lehmann, and Benny Jäger. I also want to thank the friends whohavebeenalongforthewholeride,JordanElvedahlandScottMatthews,such lastingfriendshipsburnamarkonusall,yourroleinkeepingmetetheredtoreality throughthelastdecadecannotbeunderstated. Finally, I would like to thank my future wife Maegan Kelleway. Your support andencouragementthroughoutgraduateschoolhavebeenindispensable,ultimately, you—above all others—have helped me keep a clear head through this whole process. The past 5 years especially have brought many changes to our life, and thisworkwouldn’thavebeenpossiblewithoutyou.Thisclosesonechapteronour lifeandbeginsanother,onedayatatime.