Double Resolution Model for Studying TMAO/Water Effective Interactions

The structural properties of water
molecules surrounding TMAO molecules
are studied using a newly developed atomistic force field for TMAO,
combined with a multiscale coarse-graining (MS-CG) force field derived
from the atomistic simulations. The all-atom force field is parametrized
to work with the OPLS force field and with SPC, TIP3P, and TIP4P water
models. The dual-resolution modeling enables a complete study of the
dynamical and structural properties of the system, with the CG model
providing important new physical insights into which interactions
are critical in determining the structure of water around TMAO. TMAO
is an osmolyte that stabilizes protein structures under conditions
of chemical, thermal, and pressure denaturation. This molecule is
excluded from the surface of proteins, and its effect on protein stability
is mediated through TMAO–water interactions. We find that TMAO
strongly binds two to three water molecules and, surprisingly, that
methyl groups repel both the other methyl groups of TMAO and water
molecules alike. The latter result is important because it shows that
methyl groups are not interacting with each other through the expected
hydrophobic effect (which would be attractive and not repulsive) and
that the repulsion of water molecules forces a clathrate-like hydrogen
bond network around them. We speculate that TMAO is excluded from
the vicinity of the protein because the peculiar structure of water
around TMAO prevents this molecule from coming in close contact with
the protein.