Signatures of n ->pi* interactions in proteins

Robert W. Newberry, Gail J. Bartlett, Brett VanVeller, Derek N. Woolfson*, Ronald T. Raines

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

54 Citations (Scopus)


The folding of proteins is directed by a variety of interactions, including hydrogen bonding, electrostatics, van der Waals' interactions, and the hydrophobic effect. We have argued previously that an n* interaction between carbonyl groups be added to this list. In an n* interaction, the lone pair (n) of one carbonyl oxygen overlaps with the * antibonding orbital of another carbonyl group. The tendency of backbone carbonyl groups in proteins to engage in this interaction has consequences for the structures of folded proteins that we unveil herein. First, we employ density functional theory to demonstrate that the n* interaction causes the carbonyl carbon to deviate from planarity. Then, we detect this signature of the n* interaction in high-resolution structures of proteins. Finally, we demonstrate through natural population analysis that the n* interaction causes polarization of the electron density in carbonyl groups and detect that polarization in the electron density map of cholesterol oxidase, further validating the existence of n* interactions. We conclude that the n* interaction is operative in folded proteins.

Original languageEnglish
Pages (from-to)284-288
Number of pages5
JournalProtein Science
Issue number3
Publication statusPublished - Mar 2014


  • Burgi-Dunitz trajectory
  • electron density
  • hyperconjugation
  • pyramidalization
  • stereoelectronic effect

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