Critical Assessment of the Strength of Hydrogen Bonds between the Sulfur Atom of Methionine/Cysteine and Backbone Amides in 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 center dot center dot center dot S H-bonds are compared with the representative classical sigma- and pi-type H-bonded complexes such as N-H center dot center dot center dot O, N-H center dot center dot center dot O-C and N-H center dot center dot center dot p H-bonds. With the spectroscopic, theoretical, and structural evidence, amide N-H center dot center dot center dot S H-bonds are found to be as strong as the classical sigma-type H-bonds, despite the smaller electronegativity of sulfur in comparison to oxygen. The strength of backbone-amide N-H center dot center dot center dot 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.