A Donor–Acceptor Perspective on Carbonyl–Carbonyl Interactions in Proteins

Electronic delocalization, a central concept in organic chemistry, is being invoked increasingly in biological contexts [1–3]. We have discovered a non-covalent interaction in proteins, termed the n→π* interaction, in which the lone pair (n) of the oxygen (Oi–1) of a peptide bond overlaps with the antibonding orbital (π*) of the carbonyl group (C′i=Oi) of the subsequent peptide bond (Figure 1A, B) [1]. The n→π* interaction is reminiscent of the renowned Bürgi–Dunitz trajectory [1c] and analogous to a hydrogen bond, which likewise involves the delocalization of a lone pair of an acceptor atom over the antibonding orbital (σ*) of a donor [2]. The stereochemical constraints required for an energetically meaningful n→π* interaction are met in several fundamental structural elements in proteins, including α-helices, 310 helices, and polyproline II type helices, as well as within the backbone of peptoids. A signature of the n→π* interaction is a short Oi–1··C′i contact [3]. Others have argued that the attractive C=O···C=O interaction is primarily a dipole–dipole (Figure 1C) [4] or a charge–charge interaction (Figure 1D) [5]. We used a peptidic model system (Figure 2) to explore the origin of this interaction. Regardless of the nature of the interaction between the adjacent carbonyl groups, the interaction stabilizes the trans conformation preferentially over the cis conformation. Thus, the value of Ktrans/cis reports on the strength of the C=X···C=O interaction.