Levinthal's Paradox

Alan Cai

May 24, 2024 (Last Modified May 25, 2024)

Proteins are the building blocks of life. They carry out many of the cell’s functionalities and are essential to every living thing’s survival. From facilitating metabolism to assisting movement and DNA replication, proteins work the necessary machinery to keep organisms and their cellular constituents alive.

Protein polymers are assembled from monomers known as amino acids inside a cell. Deoxyribonucleic Acid or DNA forms as the template from which genetic information to build proteins is stored. Ribonucleic acids or RNA are transcribed from DNA for translation into amino acid chains. In eukaryotes, RNA transcription occurs within the nucleus and the resulting mRNA exits the cell. In the cytosol and rough Endoplasmic Reticulum (ER), mRNA is translated into proteins with the help of ribosomes and rRNA as well as the anticodon carriers which match the amino acids, tRNA. When translation occurs, amino acids are assembled into protein chains and either begin functioning in the cell or become deposited in the rough ER for further modification.

Amino acids are primarily responsible for determining the shape of the protein. Different protein shapes determine its function. For example, hydrophobic electron chains coalesce around the center of proteins while sulfur chains form disulfide bridges.

Protein folding is a very interesting process. In the 1960s, physicist and molecular biologist Cyrus Levinthal observed that given the length of protein chains (polypeptides), the number of possible configurations would be very great, perhaps on the order of ten to three hundred according to his estimates. Thus, it is extremely unlikely that a given protein would reach the intended configuration when folded. Even if a polypeptide changed its conformation every nanosecond, it would take longer than the age of the universe for it to reach its correct form. Nevertheless, proteins appear to have no problem folding within milliseconds. This phenomenon, known as Levinthal’s Paradox, poses the intriguing question of how proteins fold.

Several explanations for how proteins fold have been proposed. Levinthal himself suggested that intended protein structures may have different energy levels than other configurations, guiding polypeptides toward the correct model. In addition, intermediary proteins or chaperonins may also play a role in helping proteins fold. Finally, Levinthal acknowledged that proteins can fold locally through secondary structures (alpha helices or beta-pleated sheets for example) before regrouping into tertiary (overall shape) arrangements.

Despite being a mostly solved contradiction, Levinthal’s paradox still serves as a healthy question for aspiring young scientists to ponder.