Persistent Link:
http://hdl.handle.net/10150/186089
Title:
Conformational studies of peptides.
Author:
Jiao, Ding.
Issue Date:
1992
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The conformational and dynamic properties of peptides play critical roles in their biological functions. Various methods have been applied for studying peptide conformations and dynamics. On the basis of structure-function studies and NMR work on the conformation of CCK, we designed a series of conformationally constrained peptides to test the hypothesis of a C-terminal folded structure required for interaction with the CCK-B receptor. Various cyclic peptides were synthesized to explore the possible spatial arrangements of key amino acid side chain groups. Based on the NMR conformational studies and receptor binding assay data, it was suggested that a C-terminal folded conformation of CCK4 is a necessary but not a sufficient structural feature for strong CCK-B receptor binding. In a series of tyrosine analogues, slow rotations around Cβ-Cγ were studied by dynamic NMR. The free energies of activation (ΔG(^≠)) at their coalescence temperatures were estimated to be in the range of 14-20 Kcal/mol. This energy barrier is comparable to the one experienced by tyrosine aromatic rings in the interior of proteins, bioactive peptides or in peptide-protein complexes. This study demonstrates the ability of conformational constraints on restricting molecular motions. These tyrosine analogues with constrained side chains can be useful tools in studying the structure-function relationships of peptides and proteins. In peptides and proteins, amino acid residues are covalently linked together by either amide bonds or disulfide bonds. The molecules Me₂S₂, N-methylacetamide and other simple amides were used as models for disulfide or peptide bond linkages in our ab initio MO studies. An angular dependence of the ¹³C and ³³S NMR chemical shifts on the C-S-S-C dihedral angle was predicted based on our calculations. The well-known syn/anti dependence of ¹³C chemical shift around the peptide bond was found to have the same origin as the angular dependence of the γ-substituent effect. A systematic geometry optimization and chemical shift calculation on a model peptide, N-acetyl-N'-methyl glycine amide, enabled us to construct the first non-empirical energy surface and ¹³C NMR chemical shift surface for this molecule. The experimentally observed correlation between ¹³C chemical shifts of Cα in amino acid residues and protein secondary structures is attributed to the effect controlled by φ and ψ dihedral angles.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Dissertations, Academic.; Chemistry, Organic.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleConformational studies of peptides.en_US
dc.creatorJiao, Ding.en_US
dc.contributor.authorJiao, Ding.en_US
dc.date.issued1992en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe conformational and dynamic properties of peptides play critical roles in their biological functions. Various methods have been applied for studying peptide conformations and dynamics. On the basis of structure-function studies and NMR work on the conformation of CCK, we designed a series of conformationally constrained peptides to test the hypothesis of a C-terminal folded structure required for interaction with the CCK-B receptor. Various cyclic peptides were synthesized to explore the possible spatial arrangements of key amino acid side chain groups. Based on the NMR conformational studies and receptor binding assay data, it was suggested that a C-terminal folded conformation of CCK4 is a necessary but not a sufficient structural feature for strong CCK-B receptor binding. In a series of tyrosine analogues, slow rotations around Cβ-Cγ were studied by dynamic NMR. The free energies of activation (ΔG(^≠)) at their coalescence temperatures were estimated to be in the range of 14-20 Kcal/mol. This energy barrier is comparable to the one experienced by tyrosine aromatic rings in the interior of proteins, bioactive peptides or in peptide-protein complexes. This study demonstrates the ability of conformational constraints on restricting molecular motions. These tyrosine analogues with constrained side chains can be useful tools in studying the structure-function relationships of peptides and proteins. In peptides and proteins, amino acid residues are covalently linked together by either amide bonds or disulfide bonds. The molecules Me₂S₂, N-methylacetamide and other simple amides were used as models for disulfide or peptide bond linkages in our ab initio MO studies. An angular dependence of the ¹³C and ³³S NMR chemical shifts on the C-S-S-C dihedral angle was predicted based on our calculations. The well-known syn/anti dependence of ¹³C chemical shift around the peptide bond was found to have the same origin as the angular dependence of the γ-substituent effect. A systematic geometry optimization and chemical shift calculation on a model peptide, N-acetyl-N'-methyl glycine amide, enabled us to construct the first non-empirical energy surface and ¹³C NMR chemical shift surface for this molecule. The experimentally observed correlation between ¹³C chemical shifts of Cα in amino acid residues and protein secondary structures is attributed to the effect controlled by φ and ψ dihedral angles.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectDissertations, Academic.en_US
dc.subjectChemistry, Organic.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairHruby, Victor J.en_US
dc.contributor.committeememberBarfield, Michaelen_US
dc.contributor.committeememberGlass, Richard S.en_US
dc.contributor.committeememberO'Brien, David F.en_US
dc.contributor.committeememberKukolich, Stephen G.en_US
dc.identifier.proquest9310598en_US
dc.identifier.oclc714172025en_US
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