Structural preferences of cysteine sulfinic acid: The sulfinate engages in multiple local interactions with the peptide backbone

Abstract

Cysteine sulfinic acid (Cys-SO2–) is a non-enzymatic oxidative post-translational modification (PTM) that has been identified in hundreds of proteins. However, the effects of cysteine sulfination are in most cases poorly understood. Cys-SO2– is structurally distinctive, with long sulfur-carbon and sulfur-oxygen bonds, and with tetrahedral geometry around sulfur due to its lone pair. Cys-SO2– thus has a unique range of potential interactions with the protein backbone which could facilitate protein structural changes. Herein, the structural effects of cysteine oxidation to the sulfinic acid were investigated in model peptides and folded proteins using NMR spectroscopy, circular dichroism, bioinformatics, and computational studies. In the PDB, Cys-SO2– shows a greater preference for α-helix than Cys. In addition, Cys-SO2– is more commonly found in structures with φ > 0, including in multiple types of β-turn. Sulfinate oxygens engage in hydrogen bonds with adjacent (i or i + 1) amide hydrogens. Over half of sulfinates have at least one hydrogen bond with an adjacent amide, and several structures have hydrogen bonds with both adjacent amides. Alternately, sulfur or either oxygen can act as an electron donor for n→π* interactions with the backbone carbonyl of the same residue, as indicated by frequent S⋯CO or O⋯CO distances below the sums of their van der Waals radii in protein structures. In peptides, Cys-SO2– favored α-helical structure at the N-terminus, consistent with helix dipole effects and backbone hydrogen bonds with the sulfinate promoting α-helix. Cys-SO2– has only modestly greater polyproline II helix propensity than Cys-SH, likely due to competition from multiple side chain-backbone interactions. Cys-SO2– stabilizes the i+1 position of a β-turn relative to Cys-SH. Within proteins, the range of side chain-main chain interactions available to Cys-SO2– compared to Cys-SH provides a basis for potential changes in protein structure and function due to cysteine oxidation to the sulfinic acid.