Role of Disulfide Bonds in Peptide and Protein Conformation

The native structures of proteins and peptides are stabilized by a number of interactions that dictate directly or indirectly the folding, conformation, and flexibility of the molecule. Most of these interactions, such as hydrogen bonds and hydrophobic interactions, are noncovalent and relatively weak. Covalent interactions, on the other hand, are generally stronger, and are thought to exert a greater influence on stability and conformation, particularly in peptides, which tend to have fewer and weaker hydrophobic interactions because of their smaller size. The most common example of a covalent interaction is the disulfide bond, formed between the sulfur atoms of two cysteine residues [1]. Disulfide bonds are typically present in extracellular proteins and peptides, such as growth factors, hormones, enzymes, and toxins, and have also been found in several thermostable intracellular proteins of archaeal microbes [2].They can play a role in covalently linking subunits in protein complexes (e.g., the heavy and light chains of antibodies or the two peptide chains of insulin) [3].Structurally, the strong covalent links formed by disulfide bonds are thought to confer additional conformational stability on proteins such as keratin that have a high disulfide content [4]. Disulfides also play a catalytic role in enzymes such as thioredoxin, which acts as a cellular redox sensor via the oxidation status of its thiol groups [5–7]. Many disulfides in proteins appear to have no direct functional role, rather their main purpose is to maintain the conformation of the protein. In certain cases, conformational changes associated with the reduction and oxidation of these bonds may allow a protein to switch between different functions [8, 9]. The relationship between disulfide bonds and the conformation of peptides and proteins is thus an intriguing one. This chapter provides a broad overview of the roles of disulfide bonds in peptides, focusing on their roles in the folding and stability of proteins, as well as how different disulfide bonding patterns and connectivity give rise to different protein topologies and conformations, and ultimately a diverse range of protein functions. An understanding of these roles also has important applications in the field of protein engineering and drug design.