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.
|Rice, Amy; Wereszczynski, Jeff (2018) Atomistic Scale Effects of Lipopolysaccharide Modifications on Bacterial Outer Membrane Defenses. Biophys J 114:1389-1399|
|Morrison, Emma A; Bowerman, Samuel; Sylvers, Kelli L et al. (2018) The conformation of the histone H3 tail inhibits association of the BPTF PHD finger with the nucleosome. Elife 7:|
|Sjodt, Megan; Macdonald, Ramsay; Marshall, Joanna D et al. (2018) Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus. J Biol Chem 293:6942-6957|
|Naziga, Emmanuel B; Wereszczynski, Jeff (2017) Molecular Mechanisms of the Binding and Specificity of Streptococcus Pneumoniae Sortase C Enzymes for Pilin Subunits. Sci Rep 7:13119|
|Bowerman, Samuel; Rana, Ambar S J B; Rice, Amy et al. (2017) Determining Atomistic SAXS Models of Tri-Ubiquitin Chains from Bayesian Analysis of Accelerated Molecular Dynamics Simulations. J Chem Theory Comput 13:2418-2429|
|Alwarawrah, Mohammad; Wereszczynski, Jeff (2017) Investigation of the Effect of Bilayer Composition on PKC?-C2 Domain Docking Using Molecular Dynamics Simulations. J Phys Chem B 121:78-88|
|Rice, A; Wereszczynski, J (2017) Probing the disparate effects of arginine and lysine residues on antimicrobial peptide/bilayer association. Biochim Biophys Acta Biomembr 1859:1941-1950|