Theoretical analysis on thermodynamic stability of chignolin

Area of Science:

• Protein thermodynamics
• Computational biophysics
• Molecular interactions

Background:

• The dominant factor in protein thermodynamic stability is an unresolved scientific challenge.
• Kauzmann's hydrophobic interaction hypothesis has been widely accepted for decades but remains unverified due to challenges in quantifying solvent effects on protein folding free energy.
• Existing theories struggle to experimentally or theoretically quantify solvent effects on protein folding free energy.

Purpose of the Study:

• To develop a computational method for identifying the primary drivers of protein thermodynamic stability.
• To investigate the contributions of intramolecular and solvent-induced interactions to protein stability using a designed protein (chignolin).

Main Methods:

• Development of a novel computational approach to extract the dominant factor in protein thermodynamic stability.
• Application of the method to chignolin, a small designed protein.
• Validation of the computational results against molecular dynamics simulations.

Main Results:

• The developed computational method yielded a free energy profile that quantitatively matched molecular dynamics simulations for chignolin.
• Decomposition analysis revealed that intramolecular interactions are the primary stabilizers of collapsed protein conformations.
• Solvent-induced interactions, including hydrophobic effects, were found to destabilize these collapsed conformations.

Conclusions:

• Intramolecular interactions play a dominant role in stabilizing protein structures.
• Solvent effects, contrary to prevailing hypotheses, tend to destabilize folded protein states.
• Findings are consistent with experimental data from globular proteins, suggesting a broader applicability of the results.