n→π* interactions in proteins

Proteins rely on a combination of intramolecular forces to form and stabilize their structures. A careful comparison of computational analysis and high-resolution crystal structures now indicates that the n→π* interaction merits inclusion in this group. Hydrogen bonds between backbone amides are common in folded proteins. Here, we show that an intimate interaction between backbone amides also arises from the delocalization of a lone pair of electrons (n) from an oxygen atom to the antibonding orbital (π*) of the subsequent carbonyl group. Natural bond orbital analysis predicted significant n→π* interactions in certain regions of the Ramachandran plot. These predictions were validated by a statistical analysis of a large, non-redundant subset of protein structures determined to high resolution. The correlation between these two independent studies is striking. Moreover, the n→π* interactions are abundant and especially prevalent in common secondary structures such as α-, 310- and polyproline II helices and twisted β-sheets. In addition to their evident effects on protein structure and stability, n→π* interactions could have important roles in protein folding and function, and merit inclusion in computational force fields.