Limited tendency of α-helical residues to form disulfide bridges: A structural explanation

Disulfide bridges have an enormous impact on the structure of a large number of proteins and polypeptides. Understanding the structural basis that regulates their formation may be important for the design of novel peptide-based molecules with a specific fold and stability. Here we report a statistical analysis of the relationships between secondary structure and disulfide bond formation, carried out using a large database of protein structures. Our analyses confirm the observation sporadically reported in previous investigations that cysteine residues located in α-helices display a limited tendency to form disulfide bridges. The very low occurrence of the disulfide bond in all α-chains compared to all β-chains indicates that this property is also evident when proteins with different topologies are investigated. Taking advantage of the large database that endorsed the analysis on relatively rare motifs, we demonstrate that cysteine residues embedded in 310 helices present a good tendency to form disulfide bonds. This result is somewhat surprising since 310 helices are commonly assimilated into α-helices. A plausible structural explanation for the observed data has been derived combining analyses of disulfide bond sequence separation and of the length of the different secondary structure elements. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.