{"id":{"repo_id":"lsu-thes","oai_identifier":"oai:repository.lsu.edu:gradschool_dissertations-1292"},"canonical_url":"https://search.dev.ndltd.org/etd/lsu-thes/oai:repository.lsu.edu:gradschool_dissertations-1292","repository":{"repo_id":"lsu-thes","name":"Lousiana State University","base_url":"https://repository.lsu.edu/do/oai/"},"display":{"title":"Incorporation of Cα,α-Disubstituted Amino Acids into Model Peptide Systems: Conformational Analysis and Possible Applications as Therapeutic Agents","abstract":"A diverse set of human diseases is associated with the misfolding of proteins into insoluble fibrillar structures that have predominantly β-sheet secondary structure. Thus it is imperative to elucidate the structural elements that contribute to β-sheet formation and stability. Peptides that autonomously form β-sheets are ideal models to study principles of protein folding and design. Gellman and coworkers first introduced an automonously folded β-hairpin (H-Arg-Tyr-Val-Glu-Val-Yyy-Xxx-Orn-Lys-Ile-Leu-Gln-NH2) that remained monomeric up to ~1 mM. Circular dichroism (CD) and nuclear magnetic resonance (NMR) analyses revealed that incorporation of non-stereogenic Aib-Xxx dipeptidyl sequences into i+1 and i+2 positions of a model peptide nucleates a stable [2:4] left-handed type-I' β-turn in aqueous buffer. The Aib-Gly dipeptidyl sequence has a backbone conformation that is superimposable on corresponding hairpins containing the DPro-Gly (type-II') and Aib-DAla (type-I') sequences. The Aib-Gly turn sequence offers an attractive approach for preparing β-hairpin peptides because it eliminates cis-trans isomerization within the β-turn region. Additionally, two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid β-protein (Aβ) that contain ααAAs at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus) were prepared. The effects of AMY-1 and AMY-2 on the aggregation of Aβ were studied, and it was determined that at stoichiometric concentrations, both peptides completely stop Aâ fibrillogenesis. Equimolar mixtures of AMY-1 and Aβ form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillic or fibrillic material even after prolonged periods of time (4.5 months). Also, 10 mole percent of AMY-1 prevented Aβ self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillic or fibrillic aggregates. AMY-2 interacts with Aβ differently in that equimolar mixtures form large (~ 1 µm) globular aggregates that do not progress to fibrils but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the peptide mitigators interfere with the native ability of Aβ to self-assemble by hydrophobic interactions either at the C-terminus or N-terminus of the molecule.","abstract_html":"A diverse set of human diseases is associated with the misfolding of proteins into insoluble fibrillar structures that have predominantly β-sheet secondary structure. Thus it is imperative to elucidate the structural elements that contribute to β-sheet formation and stability. Peptides that autonomously form β-sheets are ideal models to study principles of protein folding and design. Gellman and coworkers first introduced an automonously folded β-hairpin (H-Arg-Tyr-Val-Glu-Val-Yyy-Xxx-Orn-Lys-Ile-Leu-Gln-NH2) that remained monomeric up to ~1 mM. Circular dichroism (CD) and nuclear magnetic resonance (NMR) analyses revealed that incorporation of non-stereogenic Aib-Xxx dipeptidyl sequences into i+1 and i+2 positions of a model peptide nucleates a stable [2:4] left-handed type-I' β-turn in aqueous buffer. The Aib-Gly dipeptidyl sequence has a backbone conformation that is superimposable on corresponding hairpins containing the DPro-Gly (type-II') and Aib-DAla (type-I') sequences. The Aib-Gly turn sequence offers an attractive approach for preparing β-hairpin peptides because it eliminates cis-trans isomerization within the β-turn region. Additionally, two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid β-protein (Aβ) that contain ααAAs at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus) were prepared. The effects of AMY-1 and AMY-2 on the aggregation of Aβ were studied, and it was determined that at stoichiometric concentrations, both peptides completely stop Aâ fibrillogenesis. Equimolar mixtures of AMY-1 and Aβ form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillic or fibrillic material even after prolonged periods of time (4.5 months). Also, 10 mole percent of AMY-1 prevented Aβ self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillic or fibrillic aggregates. AMY-2 interacts with Aβ differently in that equimolar mixtures form large (~ 1 µm) globular aggregates that do not progress to fibrils but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the peptide mitigators interfere with the native ability of Aβ to self-assemble by hydrophobic interactions either at the C-terminus or N-terminus of the molecule.","abstract_has_math":false,"creators":["Etienne, Marcus A"],"institution":"Chemistry","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2008,"date_issued":"2008-01-01T08:00:00Z","date_published":"2008-01-01T08:00:00Z","updated_at":"2026-07-24T02:57:21Z","subjects":["tetrasubstituted amino acids","protien misfolding","Abeta aggregation","beta-sheets","beta-turns","beta-hairpin peptides"],"languages":[],"rights":["withheld","Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide."],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["etd-02282008-183035","https://repository.lsu.edu/gradschool_dissertations/293"],"render_values":[{"text":"etd-02282008-183035","href":null,"code":true},{"text":"https://repository.lsu.edu/gradschool_dissertations/293","href":"https://repository.lsu.edu/gradschool_dissertations/293","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.31390/gradschool_dissertations.293","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Etienne, Marcus A"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2008-01-14"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2017-03-08T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Chemistry"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["tetrasubstituted amino acids","protien misfolding","Abeta aggregation","beta-sheets","beta-turns","beta-hairpin peptides"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["withheld","Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["etd-02282008-183035","10.31390/gradschool_dissertations.293","https://repository.lsu.edu/gradschool_dissertations/293"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["A diverse set of human diseases is associated with the misfolding of proteins into insoluble fibrillar structures that have predominantly β-sheet secondary structure. Thus it is imperative to elucidate the structural elements that contribute to β-sheet formation and stability. Peptides that autonomously form β-sheets are ideal models to study principles of protein folding and design. Gellman and coworkers first introduced an automonously folded β-hairpin (H-Arg-Tyr-Val-Glu-Val-Yyy-Xxx-Orn-Lys-Ile-Leu-Gln-NH2) that remained monomeric up to ~1 mM. Circular dichroism (CD) and nuclear magnetic resonance (NMR) analyses revealed that incorporation of non-stereogenic Aib-Xxx dipeptidyl sequences into i+1 and i+2 positions of a model peptide nucleates a stable [2:4] left-handed type-I' β-turn in aqueous buffer. The Aib-Gly dipeptidyl sequence has a backbone conformation that is superimposable on corresponding hairpins containing the DPro-Gly (type-II') and Aib-DAla (type-I') sequences. The Aib-Gly turn sequence offers an attractive approach for preparing β-hairpin peptides because it eliminates cis-trans isomerization within the β-turn region. Additionally, two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid β-protein (Aβ) that contain ααAAs at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus) were prepared. The effects of AMY-1 and AMY-2 on the aggregation of Aβ were studied, and it was determined that at stoichiometric concentrations, both peptides completely stop Aâ fibrillogenesis. Equimolar mixtures of AMY-1 and Aβ form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillic or fibrillic material even after prolonged periods of time (4.5 months). Also, 10 mole percent of AMY-1 prevented Aβ self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillic or fibrillic aggregates. AMY-2 interacts with Aβ differently in that equimolar mixtures form large (~ 1 µm) globular aggregates that do not progress to fibrils but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the peptide mitigators interfere with the native ability of Aβ to self-assemble by hydrophobic interactions either at the C-terminus or N-terminus of the molecule."]},{"key":"dc:title","label":"Title","values":["Incorporation of Cα,α-Disubstituted Amino Acids into Model Peptide Systems: Conformational Analysis and Possible Applications as Therapeutic Agents"]}]}],"canonical_facts":{"dc:creator":["Etienne, Marcus A"],"dc:date":["2008-01-14"],"dc:date.available":["2017-03-08T08:00:00Z"],"dc:description.abstract":["A diverse set of human diseases is associated with the misfolding of proteins into insoluble fibrillar structures that have predominantly β-sheet secondary structure. Thus it is imperative to elucidate the structural elements that contribute to β-sheet formation and stability. Peptides that autonomously form β-sheets are ideal models to study principles of protein folding and design. Gellman and coworkers first introduced an automonously folded β-hairpin (H-Arg-Tyr-Val-Glu-Val-Yyy-Xxx-Orn-Lys-Ile-Leu-Gln-NH2) that remained monomeric up to ~1 mM. Circular dichroism (CD) and nuclear magnetic resonance (NMR) analyses revealed that incorporation of non-stereogenic Aib-Xxx dipeptidyl sequences into i+1 and i+2 positions of a model peptide nucleates a stable [2:4] left-handed type-I' β-turn in aqueous buffer. The Aib-Gly dipeptidyl sequence has a backbone conformation that is superimposable on corresponding hairpins containing the DPro-Gly (type-II') and Aib-DAla (type-I') sequences. The Aib-Gly turn sequence offers an attractive approach for preparing β-hairpin peptides because it eliminates cis-trans isomerization within the β-turn region. Additionally, two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid β-protein (Aβ) that contain ααAAs at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus) were prepared. The effects of AMY-1 and AMY-2 on the aggregation of Aβ were studied, and it was determined that at stoichiometric concentrations, both peptides completely stop Aâ fibrillogenesis. Equimolar mixtures of AMY-1 and Aβ form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillic or fibrillic material even after prolonged periods of time (4.5 months). Also, 10 mole percent of AMY-1 prevented Aβ self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillic or fibrillic aggregates. AMY-2 interacts with Aβ differently in that equimolar mixtures form large (~ 1 µm) globular aggregates that do not progress to fibrils but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the peptide mitigators interfere with the native ability of Aβ to self-assemble by hydrophobic interactions either at the C-terminus or N-terminus of the molecule."],"dc:identifier":["etd-02282008-183035","10.31390/gradschool_dissertations.293","https://repository.lsu.edu/gradschool_dissertations/293"],"dc:rights":["withheld","Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide."],"dc:subject":["tetrasubstituted amino acids","protien misfolding","Abeta aggregation","beta-sheets","beta-turns","beta-hairpin peptides"],"dc:title":["Incorporation of Cα,α-Disubstituted Amino Acids into Model Peptide Systems: Conformational Analysis and Possible Applications as Therapeutic Agents"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"],"thesis:institution_name":["Chemistry"]},"updated_at":"2026-07-24T02:57:21Z"}