Over the last two decades, enabled by progress in synchrotron radiation techniques, molecular biology methods,andcomputationalresources,therehasbeentremendousprogressindeterminingthestructure ofbiomoleculesthathasled,inmanycases,todeepstructuralinsights.Butthereisathirddimensionto biological function, namely dynamics, which is, as yet, underexplored. This has created a serious blind spot that inhibits progress towards a full understanding of macromolecular functions and biological processes. The broad objective of this proposal is to develop and utilize computer simulations that addressthisdeficiencyinknowledgebyrigorouslymodelingbiomoleculardynamicsinordertoincrease ourunderstandingofbiologicalprocesses.Morespecifically,wewillpursuethreeinterrelatedprojects. First, we will determine how chromatin remodeling factors influence the dynamics of nucleosomes and chromatinfibersasameansofregulatinggeneexpression.Second,wewillexaminethemechanismsof recognitionandregulationbysortaseenzymes,whicharekeyvirulencefactorsinGram-?positivebacteria. Finally,wewilldevelopcomputationalmethodsthatmoreeffectivelymodeltheresultsofsolutionsmall angle X-?ray scattering (SAXS) experiments for diverse biomolecular complexes. Completion of these studieswillrevealintricatedetailsabouttherelationshipbetweenthestructure,function,anddynamics ofmulticomponentbiomolecularcomplexesacrossavastrangeoftimeandlengthscales.Furthermore, thesynergybetweenthescientificgoals,aswellasthecomputationalmethodsandstrongexperimental collaborationsineachoftheseprojects,willfosternewopportunitiesandareasofscientificinquirythat theMIRAawardwillallowustopursue.Overall,thisworkwilladdressaseriesoffundamentalgapsin knowledge for critical biological processes, and will lay the foundation for future studies that will improvethetreatmentandpreventionofhumanailments.
Thebiologicalfunctionsofproteinsandnucleicacidsisaresultofboththeirthreedimensionalstructure and their conformational dynamics. In this work, computer simulations are utilized to explore and quantify these dynamic properties, as well as how they are linked to the function and regulation of biomolecular complexes. Specific projects will provide a basis for how dynamics affect DNA condensation and gene expression in chromatin fibers and substrate binding in bacterial sortase enzymes, as well as how experimental small angle X-?ray scattering experiments can be interpreted to betterunderstandthestructure/function/dynamicsrelationshipindiversebiomolecularcomplexes.
