?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F35096%2F&rft.title=STRUCTURAL+AND+FUNCTIONAL+IMPACTS+OF+CHEMICAL+MODIFICATIONS+IN+PEPTIDES+AND+SMALL+PROTEINS&rft.creator=Werner%2C+Halina&rft.description=Due+to+their+presence+in+all+forms+of+life%2C+proteins+have+remained+at+the+forefront+of+research+in+myriad+disciplines.+Chemists+employ+covalent+modifications+to+probe+protein+structure+and+function.+At+the+simplest+level+of+structure%2C+a+naturally+occurring+protein+comprises+a+linear+sequence+of+L-%CE%B1-amino+acids%2C+each+of+which+displays+one+of+twenty+sidechains.+Simple+primary+sequence+modifications+can+impact+the+complex+structure+and+function+of+proteins+in+interesting+ways.+In+this+dissertation%2C+we+document+our+efforts+to+understand+this+relationship+through+chemical+modification+of+peptides+and+small+proteins.%0D%0AThe+sequences+of+natural+proteins+can+be+partially+substituted+with+unnatural+amino+acids%2C+generating+heterogeneous-backbone+foldamers.+The+structures+and+functions+of+bioactive+proteins+have+been+recreated+by+heterogeneous-backbone+foldamers.+These+protein+mimics+show+increased+resistance+to+proteolytic+digestion%3B+however%2C+no+effort+has+yet+determined+the+relative+protection+efficiencies+of+unnatural+residues.+Thus%2C+we+ranked+the+proteolytic+protection+imparted+by+four+commonly+utilized+unnatural+residues+substituted+into+a+host+peptide.+These+rankings+have+since+been+employed+in+the+design+of+bioactive+protein+mimics.%0D%0ACovalent+cross-linking+of+protein+sidechains+is+one+type+of+modification+employed+to+stabilize+protein+structures.+Cross-links+made+across+%CE%B1-helices+are+thought+to+impart+structural+stability+by+preorganizing+the+backbone+into+an+%CE%B1-helical+conformation%3B+however%2C+there+is+limited%0D%0Aevidence+bearing+directly+on+this+hypothesis.+Thus%2C+we+compared+the+thermodynamic+impacts+of+three+cross-link+types+on+folding+in+a+small+%CE%B1-helix+rich+protein.+Our+results+support+the+preorganization+hypothesis%2C+showing+a+decreased+entropic+penalty+of+folding+for+all+three+cross-linked+proteins.+This+finding+should+help+inform+the+endeavors+of+the+peptide+and+protein+cross-linking+community.%0D%0AThe+ability+of+heterogeneous-backbone+foldamers+to+mimic+bioactive+proteins+highlights+their+potential+use+as+therapeutics.+While+our+group+has+been+developing+design+principles%2C+we+have+not+yet+achieved+structural+and+functional+mimicry+of+a+protein+larger+than+56+residues.+Thus%2C+we+use+native+chemical+ligation+to+generate+a+library+of+heterogeneous-backbone+ubiquitin+foldamers%2C+some+of+which+fold+and+function+comparably+to+native+ubiquitin.+In+addition+to+refining+our+design+principles%2C+this+is+the+first+example+of+a+heterogeneous-backbone+foldamer+of+this+size+and+functional+ability.&rft.date=2018-09-27&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F35096%2F1%2FWernerHM_ETD2018_1.pdf&rft.identifier=++Werner%2C+Halina++(2018)+STRUCTURAL+AND+FUNCTIONAL+IMPACTS+OF+CHEMICAL+MODIFICATIONS+IN+PEPTIDES+AND+SMALL+PROTEINS.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++