Everything You Need to Know About Protein Denaturation

Most proteins become functional once they acquire their native three-dimensional structure, which is dictated by the primary amino acid sequence of the protein. Denaturation is when proteins, or more specifically, nucleic acids, lose their three-dimensional structure. The occurrence of denaturation can be due to many external factors; subsequently, this event can irreversibly disrupt the protein’s functionality¹.

Forces Involved in Protein Stability

In the cell, linear polypeptides are synthesized from a sequence of mRNA through a process known as translation. As the polypeptide is synthesized, it begins to fold into its three-dimensional structure in a process known as protein folding.

The secondary structure, which includes the alpha helices and beta sheets, is stabilized by intramolecular hydrogen bonds between the amide hydrogen and carbonyl oxygen of the peptide bond that links the amino acids of the primary structure.

Interactions between side chains of amino acids that comprise the protein determine the tertiary structure. The structure is firmly maintained due to the strength of hydrophobic interactions and the disulfide that bridges the cysteine residues of the amino acids.

Lastly, the quaternary structure of a protein is determined by the interaction of the subunits of peptide chains that compose the molecule and the hydrogen bonds and hydrophobic reactions that occur between them².

Protein stability after folding is crucial for the polypeptide to perform correctly. Therefore, the cell uses diverse mechanisms to guarantee this functionality. Chaperones are a class of peptides that aid in the correct folding of other proteins by interacting with the polypeptide chain that is being synthesized, reducing possible unwanted mutations of the polypeptide³. Despite chaperone actions, some proteins still misfold; due primarily to cell mutations. For example, the protein is susceptible to misfolding when there are changes in non-covalent interactions. Studies show that misfolding or failure to fold into native structures leads to inactive proteins in almost all cases³.

The Phenomenon of Protein Denaturation

External factors such as changes in pH levels, radiation, heat, and other environmental stressors can produce mutations and cause protein denaturation. This event can affect normal cell activity and, as a result, cause the loss of protein function. Incorrect protein folding can lead to an undesirable incident known as protein aggregation, which consists of accumulating misfolded proteins inside or outside the cell. Protein aggregation can cause neurological disorders such as Alzheimer’s, Parkinson’s, and other diseases, including amyloidosis and prion disease⁴.

By measuring protein unfolding and stability, scientists can predict the onset of these diseases, among others. In addition, understanding protein behavior and stability are also very useful in developing more precise therapies to treat existing diseases. Once we know enough, we can multiply and commence protein manufacturing for every disease curable with these proteins. This is the case with many pharmaceutical drugs employed in treating various diseases. These drugs can be very sensitive to changes in production conditions, which can impact the quality, efficacy, activity, and immunogenicity of the molecule⁵.

In conclusion, understanding protein stability is crucial for identifying which exact disorder is affecting a patient and is also necessary for the design and production of stable drugs to treat diseases and/or for correcting specific regulatory folding networks.

SOURCES:

1. https://askabiologist.asu.edu/activities/breaking-proteins
2. https://www.britannica.com/science/protein/Protein-denaturation
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131146/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506414/
5. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/drug-stability