What is thought to be the dominant mechanism of protein folding? Why can it not be random?

Protein folding is the process of formation of a protein's three-dimensional structure from its amino acid sequence. It is essential for proteins to adopt their correct three-dimensional structure (called native conformation) to perform their biological functions. Misfolding can lead to protein dysfunction, causing numerous diseases such as Alzheimer's, Parkinson's, and cystic fibrosis.

Anfinsen's thermodynamic hypothesis is widely accepted as the dominant mechanism for protein folding. This hypothesis states that the native conformation of a protein is the one with the lowest free energy, meaning it is thermodynamically the most stable structure. The folding process is guided by the amino acid sequence, and the native protein structure corresponds to the global minimum of its energy landscape. Throughout this process, non-covalent interactions, such as hydrogen bonding, van der Waals forces, and hydrophobic interactions, play crucial roles in stabilizing the protein structure.

Protein folding cannot be random for several reasons: 1. Speed: If the protein folding were random, it would have to go through all possible conformational states to finally reach its native form. Considering the vast number of possibilities, this process would take an impractically long time (i.e., the "Levinthal's paradox"), while in reality, proteins fold within milliseconds to seconds. 2. Efficiency: Biological systems are known for their efficiency. A random process of protein folding would consume a large amount of energy without being efficient, which contradicts the principles of biological systems. 3. Consistency: Amino acid sequence determines the native structure of the protein. If the folding were random, the same protein sequence could adopt various conformations. However, observation shows that proteins with the same amino acid sequence fold into consistent and unique structures, leading to the same biological functions. 4. Quality control: Cells have built-in quality control mechanisms, such as chaperones and protein degradation systems, that prevent or correct misfolding. These mechanisms ensure that only properly folded proteins function in the cell. In conclusion, Anfinsen's thermodynamic hypothesis is thought to be the dominant mechanism guiding protein folding, and the folding process cannot be random due to the quick and efficient nature of the process, resulting in consistent structures and the presence of quality control mechanisms in cells.