Details

Autor(en) / Beteiligte

• Rawale, Sharad V

Titel

Configurational Control of Peptide Conformational Patterns: Design Synthesis and Conformational Analysis of Short Heterochiral Peptides

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

1997

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The enantiomeric α amino acids, with preferences for distinctive and mutually exclusive regions of the Ramachandran plot, provide promising possibilities to undertake peptide conformational motif design by allowing the preferred direction of twist at every α-carbon to be controlled in a sequence specific manner. Only a handful of the potentially feasible heteroconfigurational peptide motifs - the type II and II' β-turns, the gramicidin A β-helical channel and β-double helical pore motifs, and the Ghadiri’s nanotubular systems - are thus far known. Possible other heteroconfigurational motifs are explored in a graphical modeling study and in an experimental study by the synthesis and conformational analysis of suitable model heteroconfigurational peptide systems, and the results are presented in this thesis.A ‘helix-turn-helix’ motif is targeted in a hierarchical approach mimicking the framework model. Thus a configurationally guided type II' β-turn serving as a 310 nucleator is submitted to a range of structure modifications, while a novel 310 nucleator is engineered starting from a type II β-turn by providing D-Asp as the configurationally preferred second corner residue as well as the nucleator of a type III β-turn by forming an Asx type turn by accepting a conformation nucleating H-bond to its side chain carboxylate. The resultant ‘turn-helix’ modules, being the type II' and II β-turns serving as 310 nucleators, are assembled and the resultant decapeptides Boc-(D)Glu-Asp-Aib-Lys-Ala-Val-Pro-(D)Asp-Leu-Leu-NHMe is described as a nascent and partially developed ‘helix-turn-helix’ motif in both DMSO and water, capable of being further developed by exploiting its built-in helix template elements.Heteroconfigurational β-hairpins are envisaged in which the antiparallel strands connected in a central β-turn are of unusual molecular topology, describing motifs such as double β-helical hairpin and a circular β-hairpin with superhelical twist. Several hexa to octapeptide models of the hairpins are with an observable β-turn but devoid of hairpin like organization possibly due to the insufficient β-strand lengths. The hexapeptides Boc-Leu-(D)Val-Pro-(D)Asp(OMe)-(D)Val-Leu-NHMe is characterized crystallographically as a type II β-turn with D-configurational arms flanked by L-configuration residues with α-helical torsional angles, making it the most complex heteroconfigurational motif thus far known.