Interaction of Zwitterionic Osmolyte Trimethylamine N-oxide (TMAO) with Molecular Hydrophobes: An Interplay of Hydrophobic and Electrostatic Interactions

Interaction of trimethylamine N-oxide (TMAO) with charged/uncharged moieties of proteins and lipids is an important elementary step toward the multifaceted biofunctions of TMAO. Using minimum area Raman difference spectroscopy (MA-RDS) of aqueous TMAO (1.0 M) in the presence of deuterated molecular hydrophobes (e.g., deuterated tetramethylammonium cation (d-TMA(+)) and tert-butylalcohol (d-TBA)), we show that TMAO exhibits two distinct motifs of interaction with the cationic (d-TMA(+)) and uncharged (d-TBA) hydrophobes. Specifically, the trimethylammonium moiety of TMAO undergoes van der Waals attraction with the tert-butyl group of d-TBA, which is governed by their mutual hydrophobic interaction with water. This makes their methyl groups less exposed to water. In contrast, for the cationic hydrophobe (d-TMA(+)), TMAO interacts electrostatically via its negatively charged-oxygen, which in turn orients the TMAO-methyls away from the hydrophobe (d-TMA(+)), keeping them exposed to water.

Automated summary

The interaction between trimethylamine N-oxide (TMAO) and charged/uncharged moieties of proteins and lipids plays a crucial role in the multifaceted biofunctions of TMAO. Through minimum area Raman difference spectroscopy (MA-RDS) analysis, it was found that TMAO interacts differently with cationic and uncharged hydrophobes, influenced by van der Waals forces and electrostatic interactions, affecting the exposure of its methyl groups in water.