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

Area of Science:

• Biochemistry
• Chemical Biology
• Structural Biology

Background:

• Esters are common at peptide C-termini due to synthetic ease, despite weaker hydrogen-bonding acceptor capabilities than amides.
• Disruptions in hydrogen-bonding at peptide termini can lead to chain end-fraying, impacting overall structure.
• The specific role of C-terminal esters in promoting this fraying is often overlooked.

Purpose of the Study:

• To directly compare the influence of C-terminal ester versus amide carbonyls on peptide folding.
• To elucidate the individual contribution of these functional groups to peptide chain end-fraying.

Main Methods:

• Utilized a simple two-residue peptide fold as a model system.
• Compared the folding behavior and stability of peptides with C-terminal ester versus amide groups.

Main Results:

• Amide carbonyls significantly outperform ester carbonyls in promoting peptide folding.
• C-terminal amide groups effectively prevent peptide chain end-fraying, unlike ester groups.

Conclusions:

• Amide carbonyls are superior hydrogen-bonding acceptors for stabilizing peptide structures compared to esters.
• This finding clarifies the role of terminal functional groups in non-covalent interactions governing peptide folding and stability.