(708b) Validation of Trimethylamine-N-Oxide (TMAO) Force Fields Based on Thermophysical Properties of Aqueous Tmao Solutions

Many proteins in aqueous solution are marginally stable and the folding/unfolding equilibrium can easily be altered by the addition of small organic molecules known as co-solutes. Co-solutes that shift the equilibrium toward the unfolded ensemble are termed denaturants, whereas those that favor the folded ensemble are known as protecting osmolytes.

Protecting osmolytes such as trimethylamine N-oxide (TMAO), glycerol and sugars that push the equilibrium toward the folded ensemble play a crucial role in maintaining the function of intra-cellular proteins in extreme environmental conditions. TMAO is also used as a stabilizer in protein mutation experiments. However, a clear picture of the stabilization mechanism of TMAO has not yet been established, although there is some evidence that the mechanism is of indirect nature via modification of the properties of water [1]. It is therefore mandatory to accurately describe the behavior of aqueous TMAO solutions over a wide range of concentrations.

In this project, five different TMAO force fields are compared in terms of volumetric properties such as density and partial molar volumes, transport properties such as self-diffusion and shear viscosity, structural properties such as pair correlation functions and hydrogen bonds, as well as dielectric spectra. In addition the corresponding water model is varied for some of the TMAO force fields.

We further discuss which of the studied properties are sensitive to changes in the force field parameters or the water model, respectively, and thus suitable for further optimization of atomistic TMAO models.

[1] D. R. Canchi, A. E. Garcia, Annu. Rev. Phys. Chem., 64, 2013, 273-293.