Protein Folding

Protein Folding Thermodynamics

Summary

Protein folding is driven by the minimization of Gibbs free energy (ΔG), where the native state represents the global thermodynamic minimum. The primary driver is the hydrophobic effect, which increases solvent entropy by burying non-polar side chains away from water.

Key Points

  • 1Native state is the global free energy minimum
  • 2Hydrophobic effect is the primary driving force
  • 3Folding follows a funnel-shaped energy landscape
  • 4Proteins are marginally stable (ΔG ≈ -5 to -15 kcal/mol)

The folding of proteins from linear chains into functional three-dimensional structures is one of the most fundamental processes in biology, governed by the laws of thermodynamics.

The Thermodynamic Framework

Protein folding is driven by the minimization of Gibbs free energy (ΔG):

ΔG = ΔH - TΔS

The native state represents the global thermodynamic minimum in the protein's energy landscape. This process involves a delicate balance between:

- Enthalpy (ΔH): Contributions from hydrogen bonds, van der Waals forces, and electrostatic interactions

- Entropy (ΔS): Both conformational entropy of the protein and the entropy of the surrounding solvent

The Hydrophobic Effect

The primary driving force for protein folding is the hydrophobic effect:

  • Nonpolar amino acid side chains are thermodynamically unfavorable in aqueous solution

    • 2. Burying these residues in the protein core releases ordered water molecules

    3. This increases solvent entropy, providing the major favorable free energy contribution

    The hydrophobic effect is opposed by the loss of conformational entropy as the flexible polypeptide chain adopts a rigid, ordered structure.

    Levinthal's Paradox

    In 1969, Cyrus Levinthal noted that if a protein sampled all possible conformations randomly, folding would take longer than the age of the universe. Yet proteins fold in milliseconds to seconds. This Levinthal's Paradox demonstrates that folding cannot be a random search.

    The Folding Funnel

    The resolution to Levinthal's Paradox is the energy landscape or folding funnel model:

  • The energy landscape resembles a funnel with the native state at the bottom
  • Proteins don't sample all conformations; they follow a biased, downhill path

    • - Intermediate states (like the molten globule) represent partially folded structures

  • The "ruggedness" of the funnel determines folding kinetics and the risk of kinetic traps

    • Marginal Stability

    A key insight is that proteins are only marginally stable:

  • Typical ΔG of folding: -5 to -15 kcal/mol
  • This is the difference between many large, opposing forces
  • Marginal stability allows for conformational flexibility and regulation
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