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 α-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.

Influence of TMAO and Pressure on the Folding Equilibrium of TrpCage.

Trimethylamine--oxide (TMAO) is an osmolyte known for its ability to counteract the pressure denaturation of proteins. Computational studies addressing the molecular mechanisms of TMAO's osmolyte action have however focused exclusively on its protein-stabilizing properties at ambient pressure, neglecting the changes that may occur under high-pressure conditions where TMAO's hydration structure changes to that of increased water binding. Here, we present the first study on the combined effect of pressure and TMAO on a mini-protein, TrpCage.

Temperature induced change of TMAO effects on hydrophobic hydration.

The effect of trimethylamine-N-oxide (TMAO) on hydrophobic solvation and hydrophobic interactions of methane has been studied with Molecular Dynamics simulations in the temperature range between 280 and 370 K at 1 bar ambient pressure. We observe a temperature transition in the effect of TMAO on the aqueous solubility of methane. At low temperature (280 K), methane is preferentially hydrated, causing TMAO to reduce its solubility in water, while above 320 K, methane preferentially interacts with TMAO, causing TMAO to promote its solubility in water.

Small-to-large length scale transition of TMAO interaction with hydrophobic solutes.

We report the effect of trimethylamine N-oxide (TMAO) on the solvation of nonpolar solutes in water studied with molecular dynamics (MD) simulations and free-energy calculations. The simulation data indicate the occurrence of a length scale crossover in the TMAO interaction with repulsive Weeks-Chandler-Andersen (WCA) solutes: while TMAO is depleted from the hydration shell of a small WCA solute (methane) and increases the free-energy cost of solute-cavity formation, it preferentially binds to a large WCA solute (α-helical polyalanine), reducing the free-energy cost of solute-cavity formation a surfactant-like mechanism. Significantly, we show that this surfactant-like behaviour of TMAO reinforces the solvent-mediated attraction between large WCA solutes by means of an entropic force linked to the interfacial accumulation of TMAO.

Pressure, Peptides, and a Piezolyte: Structural Analysis of the Effects of Pressure and Trimethylamine--oxide on the Peptide Solvation Shell.

The osmolyte trimethylamine--oxide (TMAO) is able to increase the thermodynamic stability of folded proteins, counteracting pressure denaturation. Herein, we report experimental solubility data on penta-alanine (pAla) in aqueous TMAO solutions (at pH = 7 and pH = 13) together with molecular simulation data for pAla, penta-serine (pSer), and an elastin-like peptide (ELP) sequence (VPGVG) under varying pH and pressure conditions. The effect of the peptide end groups on TMAO-peptide interactions is investigated by comparing the solvation of zwitterionic and negatively charged pentamers with the solvation of pentamers with charge-neutral C- and N-termini and linear, virtually infinite, peptide chains stretched across the periodic boundaries of the simulation cell.

Molecular origin of urea driven hydrophobic polymer collapse and unfolding depending on side chain chemistry.

Osmolytes affect hydrophobic collapse and protein folding equilibria. The underlying mechanisms are, however, not well understood. We report large-scale conformational sampling of two hydrophobic polymers with secondary and tertiary amide side chains using extensive molecular dynamics simulations.