?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%2F20904%2F&rft.title=Strategies+for+Peptide+Backbone+Modification+in+Protein+Beta-Sheets&rft.creator=Lengyel%2C+George&rft.description=Design+of+foldamers%2C+unnatural+backbone+oligomers+that+mimic+the+structure+of+proteins%2C+is+an+important+field+of+research+as+these+species+can+bind+to+natural+proteins+but+are+resistant+to+proteolytic+degradation.++We+have+focused+on+developing+strategies+for+the+design+of+unnatural+oligomers+that+adopt+%CE%B2-sheet+secondary+structures+like+those+commonly+found+in+protein+tertiary+folds.+Our+approach+is+to+modify+natural+peptide+sequences+that+encode+for+%CE%B2-sheet+folds+with+various+unnatural+amino+acid+building+blocks+to+produce+hybrid-backbone+peptides+that+fold+like+the+parent+sequence+in+aqueous+solution.+%0D%0AThrough+evaluation+of+%CE%B2-hairpin+model+systems+using+multidimensional+NMR%2C+we+have+discovered+several+design+strategies+that+may+be+applicable+to+mimicry+of+sheets+found+in+larger+protein+tertiary+structures+and+have+ranked+unnatural+monomer+types+in+order+of+increasing+sheet+propensity%3A+%CE%B2-residue+%3C+N-methyl-residue+%E2%89%A4+vinylogous+%CE%B34-residue+%3C+cyclic+%CE%B3-residue.+These+substitutions+require+a+2%3A2+or+2%3A1+%CE%B1-+to+%CE%B2-residue+substitution+or+1%3A1+%CE%B1-+to+%CE%B3-+or+%CE%B1-+to+N-methyl-residue+substitution+in+order+to+maintain+native-like+folding+behavior.+%0D%0AWe+applied+these+unnatural+residue+substitutions+in+protein+GB1%2C+a+56+residue+protein+with+a+complex+tertiary+fold+consisting+of+a+four+stranded+%CE%B2-sheet+packed+against+an+%CE%B1-helix.+Using+thermal+denaturation+melts+and+circular+dichroism+spectroscopy%2C+we+have+determined+that+the+trend+of+sheet+propensity+seen+in+the+hairpin+peptide+is+similar+in+a+tertiary+fold+with+the+caveat+that+the+position+of+the+unnatural+residues+matters+greatly.+Substitution+strategies+that+lengthen+the+strands+of+the+%CE%B2-sheet+have+varying+effects+on+the+stability+of+the+folded+structure+depending+on+their+placement%3B+substitutions+near+the+center+of+the+strands+are+significantly+more+destabilizing+than+those+placed+near+the+termini.+Use+of+N%C2%AC-methylated+residues+is+not+limited+in+this+fashion%2C+but+their+positioning+must+be+chosen+so+as+to+avoid+disruption+of+inter-strand+hydrogen+bonding.+%0D%0AOverall%2C+we+have+determined+that+several+unnatural+residue+types+can+be+used+to+promote+sheet+formation+with+limited+destabilization%3B+these+residues+could+potentially+be+used+in+other+proteins+with+tertiary+folded+structures.%0D%0A&rft.date=2014-09-24&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%2F20904%2F1%2Flengyel_2014_dr3.pdf&rft.identifier=++Lengyel%2C+George++(2014)+Strategies+for+Peptide+Backbone+Modification+in+Protein+Beta-Sheets.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++