Current limitations in de novo protein structure prediction and design suggest an incomplete understanding of the interactions that govern protein folding. Here we demonstrate that previously unappreciated hydrogen bonds occur within proteins between the amide proton and carbonyl oxygen of the same residue. Quantum calculations, infrared spectroscopy, and nuclear magnetic resonance spectroscopy show that these interactions share hallmark features of canonical hydrogen bonds. Biophysical analyses demonstrate that selective attenuation or enhancement of these C5 hydrogen bonds affects the stability of synthetic beta-sheets. These interactions are common, affecting approximately 5% of all residues and 94% of proteins, and their cumulative impact provides several kilocalories per mole of conformational stability to a typical protein. C5 hydrogen bonds especially stabilize the flat beta-sheets of the amyloid state, which is linked with Alzheimer's disease and other neurodegenerative disorders. Inclusion of these interactions in computational force fields would improve models of protein folding, function, and dysfunction.
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