Principal Investigator Ronald Raines
To manifest its biological activity, the amino-acid chain of a protein must fold into a particular three-dimensional structure. In the α-helices and β-sheets that dominate protein structure, a lone pair of electrons on the oxygen atom in peptide bonds accepts a hydrogen bond. Using a variety of methods from physical organic chemistry, we have shown that the other electron pair on that oxygen atom also participates in meaningful interactions in both of these architectural elements. In an α-helix, this interaction is an C=O···C=O n→π* interaction with the next carbonyl group in the main chain. In a β-sheet, this interaction is a C=O···H–N hydrogen bond within the residue. Both of these interactions entail the formation of 5-membered rings and involve significant overlap of non-bonding and anti-bonding orbitals. Whereas the canonical hydrogen bonds engage the s orbital of the oxygen, the n→π* interaction and “C5” hydrogen bond engage a p orbital that is orthogonal to the C=O bond. These latter interactions, which are enhanced by the orbital demixing that accompanies canonical hydrogen-bond formation, have measurable effects on protein structure. We are now exploring the consequences of these unappreciated forces for the folding, stability, and aggregation of proteins.