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

• Published in: Organic & biomolecular chemistry 2013-12, Vol.11 (48), p.8348-8356
• Main Authors: Vijayadas, Kuruppanthara N, Nair, Roshna V, Gawade, Rupesh L, Kotmale, Amol S, Prabhakaran, Panchami, Gonnade, Rajesh G, Puranik, Vedavadi G, Rajamohanan, Pattuparambil R, Sanjayan, Gangadhar J
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Crystallography, X-Ray; Esters - chemistry; Hydrogen Bonding; Models, Molecular; Peptides - chemistry; Protein Folding; Protein Structure, Secondary
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c3ob41967c

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.