Structural Insights into Peptide Foldamers Containing β or γ Amino Acid Residues Gained Using NMR Spectroscopy

Abstract

The work reported in this thesis is focused on understanding the conformational properties of peptide foldamers containing β or γ amino acid residues. Chapter 1 includes a brief state-of-the-art literature review on peptide foldamers containing β and/or γ amino acids. Chapter 2 describes the effect of insertion of an Aib residue in a β3(R) peptide sequence with the help of two model peptides of comparable length- Boc-[β3(R)Val]9-OMe and Boc-[(β3(R)Val)3-Aib-(β3(R)Val)4]-OMe. Results in chapter 2 demonstrate the influence of the gem-dimethyl effect of Aib residues on the conformation of Aib/β3(S) peptides. In principle, the nature and chirality of the component residues also might affect the conformation of the heterogeneous peptides. Chapter 3 attempts to demonstrate a few of such effects with the help of NMR studies on few model peptides- (Boc-(Val)2-Ala-(Leu)2-OMe, Boc-(Val)2-β3(S)Ala-(Leu)2-OMe, Boc-(Val)2-γ4(S)Ala-(Leu)2-OMe, Boc-Val-DVal-β3(S)Ala-(Leu)2-OMe & Boc-Val-DVal-γ4(S)Ala-(Leu)2-OMe) and with a crystal structure database (CSD) analysis. Chapter 4 reports the first solution state structural characterization of C12/C14/C12 helices in peptides of the type- [γ4(R)-Aib-γ4(R)]2 and [γ4(R)-α(L)-γ4(R)]2. Δδ values of amide NHs (from DMSO-d6 titration in CDCl3) in the hexapeptides used in this study, as well as the hydrogen bond parameters and some other features of the crystal structures, reported in a previous study consistently and conclusively points to the existence of the hydrogen bond heterogeneity in C12/C14/C12 helix. Chapter 5 demonstrates the effect of insertion of a DPro-Gly segment in a γ4(R) peptide sequence using three model peptides- Boc-γ4(R)Leu-γ4(R)Leu-γ4(R)Leu-γ4(R)Leu-DPro-Gly-γ4(R)Leu-γ4(R)Leu-γ4(R)Leu-γ4(R)Leu-OMe, Boc-γ4(R)Ile-γ4(R)Ile-γ4(R)Ile-γ4(R)Ile -DPro-Gly-γ4(R)Ile-γ4(R)Ile-γ4(R)Ile-γ4(R)Ile-OMe and Boc-γ4(R)Val-γ4(R)Val-γ4(R)Val-γ4(R)Val-DPro-Gly-γ4(R)Val-γ4(R)Val-γ4(R)Val-γ4(R)Val-OMe.