Carbon bonds (C‐bonds) are the highly directional noncovalent interactions between carbonyl‐oxygen acceptors and sp3‐hybridized‐carbon σ‐hole donors through n→σ* electron delocalization. We have shown the ubiquitous existence of C‐bonds in proteins with the help of careful protein structure analysis and quantum calculations, and have precisely determined C‐bond energies. The importance of conventional noncovalent interactions such as hydrogen bond (H‐bonds) and halogen bond (X‐bonds) in the structure and function of biological molecules are well established, while carbon bonds C‐bonds have still to be recognized. We have shown that C‐bonds are present in proteins, contribute enthalpically to the overall hydrophobic interaction and play a significant role in the photodissociation mechanism of myoglobin and the binding of nucleobases to proteins.

Gas-phase vibrational spectroscopy, coupled cluster (CCSD(T)), and dispersion corrected density functional (B97-D3) methods are employed to characterize surprisingly strong sulfur center H-bonded (SCHB) complexes between cis and trans amide NH and S atom of methionine and cysteine side chain. The amide N-H···S H-bonds are compared with the representative classical σ- and π-type H-bonded complexes such as N-H···O, N-H···O═C and N-H···π H-bonds. With the spectroscopic, theoretical, and structural evidence, amide N-H···S H-bonds are found to be as strong as the classical σ-type H-bonds, despite the smaller electronegativity of sulfur in comparison to oxygen. The strength of backbone-amide N-H···S H-bonds in cysteine and methionine containing peptides and proteins are also investigated and found to be of similar magnitudes as those observed in the intermolecular model complexes studied in this work. All such SCHBs also confirm that the electronegativities of the acceptors are not the sole criteria to predict the H-bond strength.

Careful protein structure analysis unravels many unknown and unappreciated noncovalent interactions that control protein structure; one such unrecognized interaction in protein is selenium centered hydrogen bonds (SeCHBs). We report, for the first time, SeCHBs involving the amide proton and selenium of selenomethionine (Mse), i.e., amide-N-H···Se H-bonds discerned in proteins. Using mass selective and conformer specific high resolution vibrational spectroscopy, gold standard quantum chemical calculations at CCSD(T), and in-depth protein structure analysis, we establish that amide-N-H···Se and amide-N-H···Te H-bonds are as strong as conventional amide-NH···O and amide-NH···O═C H-bonds despite smaller electronegativity of selenium and tellurium than oxygen. It is in fact, electronegativity, atomic charge, and polarizability of the H-bond acceptor atoms are at play in deciding the strength of H-bonds. The amide-N-H···Se and amide-N-H···Te H-bonds presented here are not only new additions to the ever expanding world of noncovalent interactions, but also are of central importance to design new force-fields for better biomolecular structure simulations.