Amide isomerization pathways: Electronic and structural background of protonation- and deprotonation-mediated cis-trans interconversions.

The article focuses on elucidating the detailed molecular mechanism and energetics of cis-trans isomerization of amide bonds, a process critical in protein folding and function. Using high-level quantum chemical calculations on N-methylacetamide complexed with explicit water molecules, the study demonstrates that the high energy barriers (~85–150 kJ mol⁻¹) for isomerization in neutral, O-protonated, and N-deprotonated states prevent spontaneous cis-trans interconversion at room temperature. However, a novel low-energy pathway involving proton transfer from O- to N-protonation sites, facilitated by nearby water molecules, reduces the barrier to ≤11.6 kJ mol⁻¹, enabling isomerization under physiological conditions. This mechanism explains why isomerase enzymes operate via protonated amide bonds and highlights the role of aqueous proton transfers in modulating peptide bond isomerization, consistent with observed cis amide occurrences in proteins.