Hybrid Peptide Hairpins Containing α‐ and ω‐Amino Acids: Conformational Analysis of Decapeptides with Unsubstituted β‐, γ‐, and δ‐Residues at Positions 3 and 8

The effects of inserting unsubstituted -amino acids into the strand segments of model -hairpin peptides was investigated by using four synthetic decapeptides, Boc-Leu-Val-Xxx-Val-D-Pro-Gly-Leu-Xxx-Val-Val-OMe: peptide 1 (Xxx=Gly), peptide 2 (Xxx=$\beta$Gly=$\beta$ahGly=homoglycine, -$\beta$glycine), peptide 3 (Xxx=$\gamma$Abu=-$\gamma$aminobutyric acid), peptide 4 (Xxx=$\delta$Ava=-$\delta$aminovaleric acid). $^1H\hspace{2mm}NMR$ studies (500 MHz, methanol) reveal several critical cross-strand NOEs, providing evidence for -$\beta$hairpin conformations in peptides 2-4. In peptide 3, the NMR results support the formation of the nucleating turn, however, evidence for cross-strand registry is not detected. Single-crystal X-ray diffraction studies of peptide 3 reveal a -$\beta$hairpin conformation for both molecules in the crystallographic asymmetric unit, stabilized by four cross-strand hydrogen bonds, with the $\gamma$Abu residues accommodated within the strands. The D-Pro-Gly segment in both molecules (A,B) adopts a type II -$\beta$turn conformation. The circular dichroism spectrum for peptide 3 is characterized by a negative CD band at 229 nm, whereas for peptides 2 and 4, the negative band is centered at 225 nm, suggesting a correlation between the orientation of the amide units in the strand segments and the observed CD pattern.

[1]  D. Seebach,et al.  The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components , 2004 .

[2]  P. Balaram,et al.  Structure and assembly of designed beta-hairpin peptides in crystals as models for beta-sheet aggregation. , 2004, Biochemistry.

[3]  D. Seebach,et al.  Beta2-amino acids-syntheses, occurrence in natural products, and components of beta-peptides1,2. , 2004, Biopolymers.

[4]  A. C. Kunwar,et al.  Formation of β-hairpins in l-Pro-Gly containing peptides facilitated by 3-amino benzoic acid , 2003 .

[5]  I. Karle,et al.  Beta-Hairpins Generated from Hybrid Peptide Sequences Containing both Alpha- and Beta-Amino Acids , 2002 .

[6]  B. Jaun,et al.  Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve- and Ten-Membered Hydrogen-Bonded Rings , 2002 .

[7]  M. Hollósi,et al.  cis-2-aminocyclopentanecarboxylic acid oligomers adopt a sheetlike structure: switch from helix to nonpolar strand. , 2002, Angewandte Chemie.

[8]  B. Jaun,et al.  γ2‐, γ3‐, and γ2,3,4‐Amino Acids, Coupling to γ‐Hexapeptides: CD Spectra, NMR Solution and X‐ray Crystal Structures of γ‐Peptides , 2002 .

[9]  Matthew J. Mio,et al.  A field guide to foldamers. , 2001, Chemical reviews.

[10]  S. Gellman,et al.  Parallel sheet secondary structure in gamma-peptides. , 2001, Journal of the American Chemical Society.

[11]  W. DeGrado,et al.  beta-Peptides: from structure to function. , 2001, Chemical reviews.

[12]  I. Karle,et al.  Peptide hybrids containing α- and β-amino acids: Structure of a decapeptide β-hairpin with two facing β-phenylalanine residues , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  I. Karle,et al.  Designed beta-hairpin peptides with defined tight turn stereochemistry. , 2001, Biopolymers.

[14]  B. Jaun,et al.  Preparation and determination of X-ray-crystal and NMR-solution structures of γ2,3,4-peptides , 2001 .

[15]  Samuel H. Gellman,et al.  Stereochemical Control of Hairpin Formation in β-Peptides Containing Dinipecotic Acid Reverse Turn Segments , 2000 .

[16]  D. Seebach,et al.  Synthesis, Crystal Structures, and Modelling ofβ-Oligopeptides Consisting of 1-(Aminomethyl)cyclopropanecarboxylic Acid: Ribbon-Type Arrangement of Eight-Membered H-Bonded Rings , 1999 .

[17]  S. Gellman,et al.  Synthesis and Structural Characterization of Helix-Forming β-Peptides: trans-2-Aminocyclopentanecarboxylic Acid Oligomers , 1999 .

[18]  I. Karle,et al.  Hydrogen-Bonded Self-Assembled Peptide Nanotubes from Cystine-Based Macrocyclic Bisureas , 1999 .

[19]  I. Karle,et al.  Synthesis and Characterization of trans-2-Aminocyclohexanecarboxylic Acid Oligomers: An Unnatural Helical Secondary Structure and Implications for β-Peptide Tertiary Structure , 1999 .

[20]  D. Seebach,et al.  Faltblätter und Schleifen von β‐Peptiden mit proteinogenen Seitenketten , 1999 .

[21]  B. Jaun,et al.  Pleated Sheets and Turns of β-Peptides with Proteinogenic Side Chains. , 1999, Angewandte Chemie.

[22]  P. Balaram,et al.  Insertion of Methylene Units into the Turn Segment of Designed beta-Hairpin Peptides , 1999 .

[23]  S. Michnick,et al.  Design of Secondary Structures in Unnatural Peptides: Stable Helical γ-Tetra-, Hexa-, and Octapeptides and Consequences of α-Substitution , 1998 .

[24]  Douglas R. Powell,et al.  Antiparallel Sheet Formation in β-Peptide Foldamers: Effects of β-Amino Acid Substitution on Conformational Preference1 , 1997 .

[25]  B. Jaun,et al.  "Mixed" β-peptides. A unique helical secondary structure in solution. Preliminary communication , 1997 .

[26]  I. Karle,et al.  ω-Amino Acids in Peptide Design. Crystal Structures and Solution Conformations of Peptide Helices Containing a β-Alanyl-γ-Aminobutyryl Segment , 1997 .

[27]  Douglas R. Powell,et al.  Residue-based control of helix shape in β-peptide oligomers , 1997, Nature.

[28]  D. Seebach,et al.  β-Peptides: a surprise at every turn , 1997 .

[29]  P. Balaram,et al.  Omega amino acids in peptide design: incorporation into helices. , 1998, Biopolymers.

[30]  Samuel H. Gellman,et al.  β-Peptide Foldamers: Robust Helix Formation in a New Family of β-Amino Acid Oligomers , 1996 .

[31]  I. Karle,et al.  A designed beta-hairpin peptide in crystals. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Ulrich Hommel,et al.  β‐Peptides: Synthesis by Arndt‐Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X‐ray crystallography. Helical secondary structure of a β‐hexapeptide in solution and its stability towards pepsin , 1996 .

[33]  S. Awasthi,et al.  A designed beta-hairpin peptide. , 1995, Biochemical and biophysical research communications.

[34]  J. Karle,et al.  Partial structural information combined with the tangent formula for noncentrosymmetric crystals , 1968 .