Proteins fold in their functional 3D shape due to different types of interactions (Figure 1), which are related to their structure:
Hydrogen bonds determine the secondary structure of proteins. They are formed between the backbone oxygens and amide hydrogens. When the hydrogen bond occurs regularly every four amino acids, an alpha helix is formed. On the other hand, when hydrogen bonds join two strands involving alternating amino acid residues on each participating strand, a beta sheet is formed. They also play a role in forming the protein tertiary structure, as some distant amino acid residues can also interact.
Salt bridges occur in tertiary and quaternary structures. They often arise from ionizable side chains of aspartic acid, glutamic acid, arginine, and lysine, although histidine, tyrosine, and serine can also form them if the pKa favors it. Therefore, due to the numerous ionizable side chains of amino acids found throughout a protein, the pH at which a protein is placed is crucial to its stability.
Hydrophobic interactions are also found in tertiary and quaternary structures. These interactions occur between non-polar amino acid residues, leaving that part of the protein far from the contact with the solvent where the protein is. Some of these interactions are called van der Waals interactions.
Disulfide bonds are formed specifically between the thiol groups (-SH) of two cysteine amino acids. These bonds are responsible for stabilizing the globular structure, being one of the major forces responsible for holding proteins in their 3D conformation. They are found in tertiary and quaternary structures.
Figure 1. Main protein interactions.