Large Hydrogen-Bond Mismatch between TMAO and Urea Promotes Their Hydrophobic Association

Abstract

Summary Trimethylamine N -oxide (TMAO) and urea are both osmolytes found in many marine animals, yet they show opposite effects in (de-)stabilizing proteins. Gaining molecular-level insights into the TMAO-urea interaction in aqueous solution is a key step in elucidating their biological roles. Here, combined ab initio molecular dynamics simulations, polarization-resolved femtosecond infrared pump-probe spectroscopy, and nuclear magnetic resonance spectroscopy reveal that the hydrophobic interaction between TMAO and urea is favorable in comparison with the hydrogen-bonding interaction. The association of the hydrophobic methyl group of TMAO with urea is driven by the large mismatch between the strong TMAO-water hydrogen bond and the weak urea-water hydrogen bond. Our observations provide a rationale for the counteraction of osmotic pressure resulting from urea by TMAO.