Theoretical study of the effects of reversible post-translational modifications on the bond dissociation energies of amino acid C-H bonds.

Elucidating the radical reactivity of amino acid residues in peptides and proteins is crucial for understanding oxidative stress and biosynthesizing ribosomally synthesized and post-translationally modified peptides. Although the bond dissociation energy (BDE) serves as a key predictive indicator of radical susceptibility, computational studies on how reversible post-translational modifications (PTMs) modulate the BDEs of neighboring C-H bonds remain limited. In this study, I comprehensively investigated the impacts of various reversible PTMs-including phosphorylation, methylation, acylation, and supersulfidation-on the BDEs of amino acid derivative C-H bonds using density functional theory methods. The results revealed that side-chain acetylation of Lys significantly decreased the BDE of its ε C-H bond, which is rationalized by enhanced radical stabilization through spin delocalization into the acetamide group. Interestingly, while the BDE at the Lys α-position increased in the gas phase upon acetylation, it decreased in aqueous solution. Structural analyses indicated that this solvent-dependent behavior is primarily dictated by changes in the planarity of the peptide main chain, which alters the captodative effect, rather than the intrinsic electronic properties of the PTM itself. These findings provide fundamental computational insights into how reversible PTMs influence the radical reactivity and chemical stability of proteins in physiological environments.