n→π* Interactions in the Molecules of Life

Introduction Noncovalent interactions modulate the structure, function, and dynamics of the molecules of life [1]. We have discovered a noncovalent interaction in proteins and nucleic acids, termed the n→π* interaction, in which the lone pair (n) of a donor group (typically a carbonyl oxygen) overlaps with the antibonding orbital (π*) of an acceptor group (typically a carbonyl group) (Figures 1A and 1B) [2]. The n→π* interaction is reminiscent of the approach of a nucleophile to an electrophilic carbon along the Bürgi–Dunitz trajectory [2a] and analogous to a hydrogen bond, which likewise involves the delocalization of a lone pair of an acceptor over an antibonding orbital (σ*) of a donor [3]. The stereoelectronic constraints necessary for an energetically meaningful n→π* interaction are met in several fundamental protein secondary structures, such as α-, 310-, and polyproline II helices, and twisted β-sheets. A signature of the n→π* interaction in proteins is a short Oi–1···C′i contact [2b, 2d]. It has been 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 nature of this interaction. Regardless of the origin 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=O···C=O interaction.