Hydrogen bonding in protein cores — How often are unpaired donors and acceptors found in the hydrophobic interior?

Introduction:
Hydrogen bonding is a key determinant of protein stability. This question examines the prevalence of unsatisfied hydrogen bond donors or acceptors within hydrophobic cores, where burying polar groups without partners imposes a significant energetic penalty.

Given Data / Assumptions:

• A folded soluble protein in aqueous solution.
• Hydrophobic interior largely excludes water.
• Polar backbone and side chain groups prefer to form hydrogen bonds if buried.

Concept / Approach:
When a polar group is buried without a complementary partner, the desolvation penalty is high. Proteins avoid this by forming internal hydrogen bonds (for example, backbone hydrogen bonds in helices and sheets) or by keeping polar and charged groups at the surface. Therefore, unpaired donors or acceptors in the core are uncommon and usually indicate strain, catalytic requirements, or specific design features such as internal salt bridges.

Step-by-Step Solution:

Verification / Alternative check:
High resolution structures show most buried backbone NH and CO groups are paired in helices or sheets. When exceptions occur, they are often near functional sites and compensated by local networks or bound ligands to reduce the energetic cost.

Why Other Options Are Wrong:

• Only at helix ends: helix capping exists but does not confine the phenomenon to helix termini.
• Only at beta turns: polar groups appear throughout the fold, not only in turns.
• Only on Pro: Pro lacks an amide hydrogen and is not the sole determinant of unsatisfied groups.
• Frequently: contradicts fundamental energetic considerations.

Common Pitfalls:
Assuming that the hydrophobic core can tolerate many unsatisfied polar groups. In reality, a few exceptions are carefully compensated by geometry and local interactions.

Final Answer:
rarely.