Ester vs. amide on folding: a case study with a 2-residue synthetic peptide.

Although known for their inferiority as hydrogen-bonding acceptors when compared to amides, esters are often found at the C-terminus of peptides and synthetic oligomers (foldamers), presumably due to the synthetic readiness with which they are obtained using protected peptide coupling, deploying amino acid esters at the C-terminus. When the H-bonding interactions deviate from regularity at the termini, peptide chains tend to "fray apart". However, the individual contributions of C-terminal esters in causing peptide chain end-fraying goes often unnoticed, particularly due to diverse competing effects emanating from large peptide chains. Herein, we describe a striking case of a comparison of the individual contributions of C-terminal ester vs. amide carbonyl as a H-bonding acceptor in the folding of a peptide. A simple two-residue peptide fold has been used as a testing case to demonstrate that amide carbonyl is far superior to ester carbonyl in promoting peptide folding, alienating end-fraying. This finding would have a bearing on the fundamental understanding of the individual contributions of stabilizing/destabilizing non-covalent interactions in peptide folding.

Carboxamide versus sulfonamide in peptide backbone folding: a case study with a hetero foldamer.

Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bonding pattern and backbone helical handedness differ diametrically.

Orthanilic acid-promoted reverse turn formation in peptides.

Orthanilic acid (2-aminobenzenesulfonic acid, (S)Ant), an aromatic ß-amino acid, has been shown to be highly useful in inducing a folded conformation in peptides. When incorporated into peptide sequences (Xaa-(S)Ant-Yaa), this rigid aromatic ß-amino acid strongly imparts a reverse-turn conformation to the peptide backbone, featuring robust 11-membered-ring hydrogen-bonding.

An unusual conformational similarity of two peptide folds featuring sulfonamide and carboxamide on the backbone.

Two folded peptides featuring carboxamide and sulfonamide at the core of the peptide fold have been shown to possess almost similar conformational features, despite the well-known fact that carboxamides and sulfonamides have strikingly different hydrogen-bonding and geometrical preferences.

Helical folding in heterogeneous foldamers without inter-residual backbone hydrogen-bonding.

This communication describes a set of hybrid foldamers that do not feature inter-residual, but intra-residual backbone hydrogen-bonding, yet adopt a preferentially folded conformation displaying right-handed helical architecture. Conformational ordering is apparently due to the combined conformational restrictions imposed by the conformationally restricted individual amino acid residues with which the oligomers are made of.