Protein Folding

Overview

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation which is critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.

Protein Structure Is Critical to Its Biological Function

Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing immunological defense, storage, transport, cellular communication, movement, and structural support. A protein’s function mostly depends on its ability to recognize and bind other molecules, analogous to a lock and key. Hence the specific activity of each protein depends on its unique three-dimensional architecture.

For a protein to be functional, it must fold accurately. Most proteins go through several intermediate forms before folding into the most stable, biologically active structure. Misfolding of proteins has detrimental effects on the overall functioning of the cell. In humans, several diseases are due to the accumulation of misfolded or unfolded proteins. These include cystic fibrosis, Alzheimer’s, Parkinson’s, ALS, and Creutzfeldt-Jakob disease.

Key Determinants of Protein Structure

Proteins are made up of one or more chains of amino acids, called polypeptides. A polypeptide is synthesized as a linear chain which rapidly folds upon itself to form a three-dimensional structure. The term polypeptide and protein are sometimes used interchangeably, but most commonly, a folded polypeptide that can perform a biological function is called a protein. A protein structure is usually described on four levels: primary, secondary, tertiary, and quaternary. Most polypeptides fold into an overall compact, globular tertiary structures, such as hemoglobin, the oxygen-carrying protein in the blood. Some proteins, like keratins, can form long fibers that are commonly found in hair and nails.

The sequence of amino acids in the polypeptide chain is the primary determinant of its structure. The amino acid sequence determines the type and location of secondary structures. Additionally, the overall tertiary structure of a protein is predominantly stabilized by chemical bonds between amino acid side chains—the unique chemical groups that distinguish amino acids from each other. These side chains are either positively or negatively charged, polar uncharged, or non-polar.

The amino acids have unique physical and chemical characteristics depending on their side chain groups. For example, polar and charged amino acids interact with water to form hydrogen bonds and are called hydrophilic; whereas the non-polar amino acids avoid interactions with water and are called hydrophobic. Hence when a protein is folded in a cellular environment, side chains of hydrophobic amino acids are buried in the core of the protein away from the aqueous surroundings, whereas the hydrophilic amino acids side chains are exposed on the surface of the protein.

The tightly packed hydrophobic amino acids in the protein core lead to the formation of weak Van der Waals interactions between the side chains groups. Presence of these Van der Waals forces impart added stability to the folded protein. The polar amino acids exposed on the surface of the protein are free to form hydrogen bonds with water molecules or other polar amino acid side chains. The positively and negatively charged amino acids are also present on a protein’s exterior where they form ionic bonds with other nearby, oppositely charged amino acids.

Disulfide bonds form between two sulfhydryl, or SH, groups on the amino acid cysteine. This is a very robust interaction which acts like reinforcement on the folded protein. The presence of disulfide bonds locks the folded protein in its most favored three-dimensional conformation. Proper folding of a protein also depends on other factors of cellular environment like pH, salt concentration, temperature, etc. Alteration of the physical and chemical conditions in a protein environment affect the chemical interactions holding the protein together and can cause the protein to misfold or unfold and lose its biological function—a process known as protein denaturation.