5.3 : Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, 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 recognizing and binding 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. Protein misfolding can impair the overall functioning of the cell. Accumulation of misfolded or unfolded proteins in humans leads to cystic fibrosis, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease.

Critical 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 that rapidly folds upon itself to form a three-dimensional structure. The terms 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 structure, such as hemoglobin, the oxygen-carrying protein in the blood. Some proteins like keratins form long fibers and are commonly found in hair and nails. Globular proteins are soluble in water, unlike fibrous proteins.

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 charged (positively or negatively), 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. In contrast, 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. In contrast, the hydrophilic amino acid side chains are exposed on the protein's surface.

The tightly packed hydrophobic amino acids in the protein core lead to the formation of weak Van der Waals interactions between the side chain groups. These Van der Waals forces impart added stability to the folded protein. The polar amino acids exposed on the protein's surface 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 sulfhydryls, or SH, groups on the amino acid cysteine. This is a robust interaction that acts like reinforcement on the folded protein. Disulfide bonds lock the folded protein in its most favored three-dimensional conformation. Proper folding of a protein also depends on other factors of the cellular environment like pH, salt concentration, temperature, etc. Alteration of the physical and chemical conditions in a protein environment affects 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.