Folding thermodynamics — Which factor is most unfavorable during protein folding?

Introduction:
Protein folding reflects a competition between favorable and unfavorable contributions to free energy. This question asks which factor opposes folding the most, highlighting the entropic cost of ordering a flexible polypeptide chain.

Given Data / Assumptions:

• Folding is considered under aqueous, near physiological conditions.
• Forces include hydrophobic effect, van der Waals packing, electrostatics, and covalent crosslinks.
• Conformational entropy refers to the loss of chain configurational freedom upon folding.

Concept / Approach:
The free energy of folding can be sketched as ΔG_fold = ΔH - T*ΔS. Hydrophobic interactions, van der Waals contacts, electrostatic pairs, and disulfide bonds generally contribute favorable enthalpy or solvent entropy. In contrast, restricting the chain from a vast ensemble of unfolded conformations to a single native state yields a large negative entropy change for the polypeptide, which is unfavorable (increases ΔG).

Step-by-Step Solution:

Verification / Alternative check:
Calorimetric measurements and computational models consistently require large favorable terms to offset the chain entropy cost, which explains marginal stability and temperature sensitivity of many proteins.

Why Other Options Are Wrong:

• Hydrophobic interactions: major favorable driver of folding.
• Van der Waals interactions: favorable packing in the core.
• Electrostatic interactions: often favorable through salt bridges and dipole interactions, though context dependent.
• Disulfide bonds: covalent crosslinks stabilize the folded state.

Common Pitfalls:
Confusing solvent entropy with chain entropy. Hydrophobic collapse increases solvent entropy even while chain entropy decreases.

Final Answer:
Conformational entropy.