Cosolvent effects on protein stability

Area of Science:

• Biochemistry
• Chemical Physics

Background:

• Proteins exhibit marginal stability, sensitive to solution conditions.
• Cosolvents alter protein folding equilibrium; denaturants destabilize, protecting osmolytes stabilize.
• Urea is a common denaturant, its mechanism debated; Trimethylamine N-oxide (TMAO) is a stabilizing osmolyte with an unclear mechanism.

Purpose of the Study:

• To review experimental and computational findings on urea's protein denaturation mechanism.
• To elucidate the molecular mechanism of protein stabilization by Trimethylamine N-oxide (TMAO).
• To develop and present a computational model for TMAO interactions.

Main Methods:

• Review of recent experimental studies on protein cosolvent interactions.
• Analysis of computational studies, including detailed molecular simulations.
• Development of a force field model for TMAO incorporating its water interactions.

Main Results:

• Emerging consensus indicates urea directly interacts with protein peptide backbones and side chains.
• TMAO exhibits strong interactions with water, influencing its effect on proteins.
• A new TMAO model provides physical insight into cosolvent-cosolvent interactions and protein binding.

Conclusions:

• Urea's denaturation mechanism involves direct favorable interactions with protein structures.
• TMAO stabilizes proteins likely through complex hydration shell interactions, not direct protein binding.
• Computational models incorporating detailed water-cosolvent interactions are crucial for understanding osmolyte effects.