TMAO-Protein Preferential Interaction Profile Determines TMAO's Conditional In Vivo Compatibility

Area of Science:

• Biochemistry
• Chemical Biology
• Thermodynamics

Background:

• Trimethylamine N-oxide (TMAO) is a metabolite linked to atherosclerosis.
• The precise mechanisms by which TMAO influences protein behavior and proteostasis are not fully understood.
• Understanding TMAO's interactions is crucial for its biological and pathological implications.

Purpose of the Study:

• To experimentally characterize the preferential interaction potential of TMAO with proteins.
• To elucidate the thermodynamic basis for TMAO's effects on protein processes.
• To differentiate TMAO's stabilizing effects from other osmolytes.

Main Methods:

• Thermodynamic analysis of TMAO-protein interactions.
• Experimental characterization of TMAO's preferential exclusion from protein surfaces.
• Investigation of TMAO's impact on protein unfolding and aggregation (Aβ42).

Main Results:

• TMAO is preferentially excluded from most protein surfaces, especially hydrophobic regions exposed upon unfolding.
• This exclusion explains TMAO's potent globular protein stabilization.
• TMAO's interaction profile counteracts urea's effects and promotes amyloidogenic peptide aggregation.

Conclusions:

• TMAO's interaction profile dictates its role as a chemical chaperone and its conditional compatibility in vivo.
• The study provides a thermodynamic framework for understanding TMAO's biological significance and pathological impact.
• Controlling in vivo solute concentrations is critical due to the pathological potential of solutes like TMAO.