Primary steps in the reaction of OH radicals with peptide systems: perspective from a study of model amides.

This study reports on an ab initio investigation into the effects of radical attack on peptide backbones using eight model amides. The eight model amides are divided into two subcategories, formamide and acetamide. Within each subcategory, there are four unique systems which include the parent, cis and trans methyl, and the dimethyl structures. The mechanism for hydrogen abstraction shows alpha-C abstraction is kinetically and thermodynamically favorable for all formamide systems. The addition of a methyl group on the nitrogen results in a secondary competitive pathway at the gamma-C site. In the parent acetamide, beta-abstraction is preferred. The addition of a methyl group on the amino group of acetamide results in the introduction of a secondary pathway that will outcompete beta-abstraction, both thermodynamically and kinetically. For all systems, H-abstraction off the nitrogen is the least preferred path. With the addition of a methyl group on the nitrogen, H-abstraction off the nitrogen becomes more favorable. To explain site preference, geometry structures and stabilizations are examined. The results of this study have implications for future studies on radical attack of peptide and protein systems.