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Design and synthesis of novel nonpolar host peptides for the determination of the 3 10 ‐ and α‐helix compatibilities of α‐amino acid buildig blocks: An assessment of α,α‐disubstituted glycines
Author(s) -
Obrecht Daniel,
Altorfer Michael,
Bohdal Udo,
Daly John,
Huber Walter,
Labhardt Alexander,
Lehmann Christian,
Müller Klaus,
Ruffieux Ruth,
Schönholzer Peter,
Spiegler Clive,
Zumbrunn Cornelia
Publication year - 1997
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/(sici)1097-0282(19971015)42:5<575::aid-bip7>3.0.co;2-n
Subject(s) - chemistry , peptide , amino acid , helix (gastropod) , stereochemistry , crystallography , biochemistry , snail , biology , ecology
The present work describes three novel nonpolar host peptide sequences that provide a ready assessment of the 3 10 ‐ and α‐helix compatibilities of natural and unnatural amino acids at different positions of small‐ to medium‐size peptides. The unpolar peptides containing Ala, Aib, and a C‐terminal p‐iodoanilide group were designed in such a way that the peptides could be rapidly assembled in a modular fashion, were highly soluble in solvent mixtures of triflouroethanol and H 2 O for CD‐ and two‐dimensional (2D) nmr spectroscopic analyses, and showed excellent crystallinity suited for x‐ray structure analysis. To validate our approach we synthesized 9‐mer peptides 79a–96 (Table IV), 12‐mer peptides 99–110c (Table V), and 10‐mer peptides 120a–125d and 129–133 (Table VI and Scheme 8) incorporating a series of optically pure cyclic and open‐chain (R)‐ and (S)‐α,α‐disubstituted glycines 1–10 (Figure 2). These amino acids are known to significantly modulate the conformations of small peptides. Based on x‐ray structures of 9‐mers 79a, 80, and 87 (Figures 4–7), 10‐mers 124c, 131, and 132 (Figures 9–12), and 12‐mer peptide 102b (Figure 13), CD spectra of all peptides recorded in acidic, neutral, and basic media and detailed 2D‐nmr analyses of 9‐mer peptide 86 and 12‐mer 102b, several interesting conformational observations were made. Especially interesting results were obtained using the convex constraint CD analysis proposed by Fasman on 9‐mer peptides 79a–d, 80, 81, 86, and 87, which allowed us to determine the relative content of 3 10 ‐ and α‐helical conformations. These results were fully supported by the corresponding x‐ray and 2D‐nmr analyses. As a striking example we found that the (S)‐ and (R)‐β‐tetralin derived amino acids (R)‐ and (S)‐1 show excellent α‐helix stabilisation, more pronounced than Aib and Ala. These novel reference peptide sequences should help establish a scale for natural and unnatural amino acids concerning their intrinsic 3 10 ‐ and α‐helix compatibilities at different positions of medium‐sized peptides and thus improve our understanding in the folding processes of peptides. © 1997 John Wiley & Sons, Inc. Biopoly 42: 575–626, 1997