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J Am Chem Soc. 2009 Jun 3;131(21):7244-6. doi: 10.1021/ja901188y.

Nature of amide carbonyl--carbonyl interactions in proteins.

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Graduate Program in Biophysics, University of Wisconsin, Madison, Wisconsin 53706, USA.


Noncovalent interactions define and modulate biomolecular structure, function, and dynamics. In many protein secondary structures, an intimate interaction exists between adjacent carbonyl groups of the main-chain amide bonds. As this short contact contributes to the energetics of protein conformational stability as well as protein-ligand interactions, understanding its nature is crucial. The intimacy of the carbonyl groups could arise from a charge-charge or dipole-dipole interaction, or n-->pi * electronic delocalization. This last putative origin, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (O(i-1)) of a peptide bond over the antibonding orbital (pi*) of the carbonyl group (C(i)=O(i)) of the subsequent peptide bond. By installing isosteric chemical substituents in a peptidic model system and using NMR spectroscopy, X-ray diffraction analysis, and ab initio calculations to analyze the consequences, the intimate interaction between adjacent carbonyl groups is shown to arise primarily from n-->pi* electronic delocalization. This finding has implications for organic, biological, and medicinal chemistry.

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