Entropic stabilization of proteins by TMAO

Area of Science:

• Biochemistry
• Chemical Biology
• Computational Biology

Background:

• Trimethylamine N-oxide (TMAO) is an osmolyte that stabilizes proteins against osmotic stress.
• Understanding TMAO's mechanism requires investigating its interactions with protein fragments.

Purpose of the Study:

• To elucidate the residue-specific interactions of TMAO with model dipeptides.
• To investigate TMAO's effect on intrinsically disordered peptides and protein stabilization.

Main Methods:

• Molecular dynamics simulations of TMAO with model dipeptides (L2, S2, Q2, K2, G2) and Aβ(16-22).
• Analysis of TMAO's hydrogen bonding preferences and effects on peptide conformation.

Main Results:

• TMAO preferentially hydrogen bonds with the peptide backbone, not side chains, except for lysine.
• TMAO depletion from longer peptides (G6) suggests chain length relevance.
• TMAO induces compact and α-helical structures in intrinsically disordered Aβ(16-22) peptides.

Conclusions:

• TMAO stabilizes proteins by surface depletion, favoring intramolecular interactions over TMAO-backbone interactions.
• TMAO acts as a nanocrowding agent, promoting protein stabilization through excluded volume effects.
• TMAO induces a cooperative coil-to-helix transition in disordered peptides, similar to crowded environments.