Coarse-grained strategy for modeling protein stability in concentrated solutions.

Area of Science:

• Biophysics
• Computational Biology
• Protein Chemistry

Background:

• Protein thermodynamic stability is crucial for function.
• Understanding protein behavior in concentrated solutions is challenging.
• Factors influencing protein stability include sequence, concentration, and solution conditions.

Purpose of the Study:

• To model the thermodynamic stability of single-domain globular proteins in concentrated aqueous solutions.
• To investigate the relationship between protein sequence hydrophobicity, protein-protein interactions, and native-state stability.
• To explore the impact of protein concentration on stability.

Main Methods:

• Developed a coarse-grained model.
• Derived effective protein-protein interactions from native and denatured states.
• Utilized heteropolymer collapse theory to calculate folding thermodynamics from sequence information.
• Employed Reactive Canonical Monte Carlo simulations.

Main Results:

• Model predicts sequence hydrophobicity modulates the effect of protein concentration on native-state stability.
• Low hydrophobicity proteins are stabilized by increased concentration.
• High hydrophobicity proteins show complex, non-monotonic stability behavior with concentration.
• Results align qualitatively with experimental observations.

Conclusions:

• Protein concentration significantly influences protein stability in solution.
• Hydrophobic interactions and entropic crowding effects compete to determine stability.
• Sequence-derived hydrophobicity is a key determinant of protein concentration-dependent stability.