Hydrophobicity and folding: what does the correlation between ΔG of transfer (aqueous → organic) and solvent-accessible surface area (SASA) of amino acid residues tell us?

Introduction:
Empirical hydrophobicity scales often derive from the free energy change for transferring residues or analogs from water to an organic phase. Correlating these ΔG values with solvent-accessible surface area (SASA) informs how burial of surfaces contributes to folding.

Given Data / Assumptions:

• ΔG(transfer) approximates residue hydrophobicity.
• SASA decreases upon burial inside the folded core.
• Peptide backbone and side chains both contribute to solvation energetics.

Concept / Approach:

During folding, hydrophobic surface area is buried, reducing unfavorable interactions with water and releasing structured water, which contributes to favorable ΔG. The correlation between ΔG(transfer) and area emphasizes surface burial as a central term.

Step-by-Step Solution:

Verification / Alternative check:

Fold stability often scales with hydrophobic core size; mutation studies that increase exposed hydrophobic area typically destabilize proteins.

Why Other Options Are Wrong:

Limiting to polar residues ignores dominant nonpolar contributions; peptide bond terms can be accounted for; SDS denaturation exposes surfaces (opposite of folding); electrostatics alone cannot explain the broad correlation.

Common Pitfalls:

Overinterpreting ΔG(transfer) without considering context (backbone, specific interactions, temperature).

Final Answer:

It reflects the reduction in solvent-accessible area during protein folding