Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

Abstract

Carbonyl-carbonyl n→π* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the π* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a “reciprocal” carbonyl-carbonyl interaction with substantial back and forth n→π* and π→π* electron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding.

Noncovalent Carbon‐Bonding Interactions in Proteins

“…There is substantial donor–acceptor orbital overlap that is, the overlap between the oxygen lone pair orbital (n) with the antibonding sigma orbital of C‐Z (σ*). The n O →σ* C‐Z interaction energies are very similar to those of two n→π* interaction energies observed through reciprocal C=O⋅⋅⋅C=O interaction . Hence, we would like to draw attention to the fact that one n O →σ* C‐Z interaction is equivalent to two n→π* interactions, thus confirming that C‐bonds are strong and viable in proteins.…”

Crystal Structure and Hirshfeld Surface Analysis of Diethyl (6-methyl-2-pyridyl)aminoethylenemalonate

“…This is likely the result of a carbonyl-carbonyl stacking interaction. Such interactions have been found in other small molecules and the secondary structures of proteins, and are the result of n → π* and π → π* interactions [17]. There is also a short contract between H3 and C11 (2.817 Å).…”

Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units

“…Two or three cumulative n → π * strengthening may explain discussed difference in the calculated value for the dimer and the observed magnitude for the oligomers in solution. Reciprocal carbonyl-carbonyl interactions recently discovered in polyproline II (PPII) helices (Rahim et al, 2017 ) may also be factor of the stabilization of E isomers.…”