Protein folding

Lore & Background

The folding of many proteins begins even during the translation of the polypeptide chain. The amino acids interact with each other to produce a well-defined three-dimensional structure, known as the protein's native state. This structure is determined by the amino-acid sequence or primary structure. Formation of secondary structure, such as alpha helices and beta sheets, is the first step in the folding process, stabilized by intramolecular hydrogen bonds as characterized by Linus Pauling. The alpha helices and beta sheets are commonly amphipathic, helping form tertiary structure where hydrophilic sides face the aqueous environment and hydrophobic sides face the protein's core. Tertiary structure may give way to quaternary structure in some proteins, involving the assembly of subunits that have already folded.

Reader's Guide

Protein folding is a spontaneous process mainly guided by hydrophobic interactions, formation of intramolecular hydrogen bonds, and van der Waals forces, opposed by conformational entropy. The hydrophobic effect, where hydrophobic chains collapse into the protein core away from water, is a key driving force. Minimizing hydrophobic side-chains exposed to water is important for folding. The folding time scale varies dramatically: very small single-domain proteins up to a hundred amino acids typically fold in a single step within milliseconds, while the slowest folding proteins require many minutes or hours due to proline isomerization. Understanding and simulating protein folding has been an important challenge for computational biology since the late 1960s. Failure to fold into a native structure generally produces inactive proteins, but misfolded proteins can have modified or toxic functionality, with several neurodegenerative diseases believed to result from accumulation of amyloid fibrils formed by misfolded proteins, including prions.

Did You Know?

• The folding of many proteins begins even during the translation of the polypeptide chain.
• The fastest known protein folding reactions are complete within a few microseconds.
• Denaturation of proteins is a transition from a folded to an unfolded state, occurring in cooking, burns, and proteinopathies.
• Many allergies are caused by incorrect folding of some proteins because the immune system does not produce antibodies for certain protein structures.