Signatures of n[arrow right][pi] interactions in proteins

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[arrow right]π* interaction between carbonyl groups be added to this list. In an n[arrow right]π* interaction, the lone pair (n) of one carbonyl oxygen overlaps with the π* 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[arrow right]π* interaction causes the carbonyl carbon to deviate from planarity. Then, we detect this signature of the n[arrow right]π* interaction in high-resolution structures of proteins. Finally, we demonstrate through natural population analysis that the n[arrow right]π* 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[arrow right]π* interactions. We conclude that the n[arrow right]π* interaction is operative in folded proteins. [PUBLICATION ABSTRACT]