A unique piezolyte mechanism of TMAO: Hydrophobic interactions under extreme pressure conditions

We report a computer simulation study of the effect of trimethylamine N-oxide (TMAO) on the pressure stability of the hydrophobic contact interaction of two nonpolar alpha-helices. We found that TMAO counterbalanced the disruptive effect of pressure destabilization on account of an earlier reported electronic polarization effect that led to an increased TMAO dipole moment under compression of the solvent. This direct stabilization mechanism became ineffective when the dipole polarization of TMAO was not considered and was linked to nonspecific van der Waals interactions of TMAO with the nonpolar surfaces of the two helices, which became weaker as TMAO became stronger polarized at high pressure. The corresponding thermodynamic driving forces are discussed and should be generic for hydrophobic interactions under high pressure. The proposed mechanism suggests that TMAO stands out as a piezolyte among stabilizing osmolytes, potentially protecting biological assemblies formed by hydrophobic interactions under extreme pressure conditions. (c) 2022 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study investigates the effect of trimethylamine N-oxide (TMAO) on the pressure stability of hydrophobic contact interaction in nonpolar alpha-helices through computer simulations. The results indicate that TMAO counteracts the disruption caused by pressure destabilization by increasing the dipole moment of TMAO under solvent compression. This direct stabilization mechanism becomes ineffective without considering the dipole polarization of TMAO and is associated with nonspecific van der Waals interactions between TMAO and the nonpolar surfaces of the helices, which weaken as TMAO becomes more polarized under high pressure. The findings have implications for hydrophobic interactions under high pressure and suggest that TMAO stands out as a piezolyte among stabilizing osmolytes, potentially protecting biological assemblies formed by hydrophobic interactions under extreme pressure conditions.