What are the enthalpic and entropic factors that lead to the stabilization of a protein upon protein folding?

Enthalpy (H) is a measure of the total heat content in a system, while entropy (S) is a measure of the disorder or randomness within a system. In the context of protein folding, enthalpic contributions come mainly from the formation of weak non-covalent interactions, while entropic contributions arise due to the increase in solvent entropy upon folding.

In protein folding, enthalpic factors are generally favorable for protein stabilization. These factors include: 1. Formation of hydrogen bonds: When a protein folds, hydrogen bonds form between polar amino acid side chains and the protein backbone, leading to a decrease in free energy (∆G), which stabilizes the folded conformation. 2. Hydrophobic interactions: The nonpolar amino acid side chains tend to cluster in the core of the protein, minimizing contact with water and maximizing van der Waals attractive forces between them. This process also contributes to protein stabilization by lowering the free energy (∆G) of the folded state. 3. Ionic interactions: Favorable electrostatic interactions between charged amino acid side chains (positive and negative charges) can also contribute to protein stabilization upon folding.

In protein folding, entropic factors are generally unfavorable for protein stabilization because folding leads to a decrease in conformational entropy when a disordered chain adopts an ordered, structured conformation. However, another important entropic contribution to protein folding comes from the increase in solvent (water) entropy, which is favorable for protein stabilization: 1. Release of water molecules: When a protein folds, the hydrophobic side chains are sequestered in the protein core, allowing the surrounding water molecules to form more hydrogen bonds with each other and increasing the entropy of the solvent. 2. Increased translational entropy: The folded protein decreases the excluded volume of the solvent and increases the translational entropy of water molecules. So, although the folding of a protein leads to a decrease in conformational entropy, this is compensated by the favorable increase in solvent entropy, resulting in a net decrease in free energy (∆G) for the folded state. In conclusion, enthalpic factors such as hydrogen bonding, hydrophobic interactions, and ionic interactions lead to favorable contributions to protein stabilization upon folding, while the entropic factor of solvent entropy also contributes to protein folding stability. The overall protein stabilization is determined by the balance between enthalpic and entropic factors.