Driving forces of folding — Which interaction is generally the most favorable contributor to protein folding?

Introduction:
Several interactions stabilize the native state of proteins. This question targets the principal favorable driver that pushes nonpolar residues into the core and shapes the overall fold in aqueous environments.

Given Data / Assumptions:

• Folding occurs in water at near physiological conditions.
• Interactions considered include hydrophobic effect, hydrogen bonding, van der Waals, and others.
• Focus is on overall free energy contribution rather than local specificity.

Concept / Approach:
The hydrophobic effect is largely entropic from the solvent perspective. Aggregating nonpolar surfaces reduces the structured water shell, releasing water molecules to the bulk and increasing solvent entropy, which strongly favors folding. Other forces such as hydrogen bonds and van der Waals contacts refine the fold and add stability but are often compensatory because similar interactions exist in the unfolded state with water.

Step-by-Step Solution:

Verification / Alternative check:
Mutational studies show that substituting hydrophobic core residues with polar or smaller residues often destabilizes the fold more than disrupting individual hydrogen bonds, highlighting the dominant role of hydrophobic burial.

Why Other Options Are Wrong:

• Conformational entropy: unfavorable for folding.
• Van der Waals: favorable but typically secondary to hydrophobic driving force.
• Hydrogen bonds: important for specificity and structure, but many are exchanged with water in the unfolded state.
• Disulfide bonds: stabilizing but not universal; many proteins fold without them.

Common Pitfalls:
Equating hydrogen bonding with the main folding driver. Hydrogen bonds are essential for secondary structure but the hydrophobic effect largely powers the global collapse.

Final Answer:
Hydrophobic interactions.