Influence of Trimethylamine N-Oxide (TMAO) on the Three-dimensional Distribution and Alignment of Solvent Molecules in Aqueous Solution

Abstract

By means of Monte Carlo simulations together with an ab initio molecular orbital method, we present the influence of trimethylamine N-oxide (TMAO), which is a highly polarized spherical-polyhedron, on the distribution and the alignment of surrounding water molecules. The specific alignment of the average dipole moments of solvent water around TMAO is observed in the MC simulation. The number of water molecules in the first hydration shell from MC simulation was in good agreement with the experimental value. A cluster model of TMAO with 12 water molecules was presented as a representative hydration structure of TMAO.Trimethylamine N-oxide (TMAO, Figure 1a) is one of the well-known osmolytes that play an important role in maintaining osmotic equilibria in living cells.1 TMAO also plays a prominent in stabilizing protein structure.2 Although many experimental and theoretical investigations have been carried out using different techniques to understand the characteristics of TMAO, the molecular mechanism by which TMAO functions is not completely known yet. Hydration structure around TMAO, especially around the methyl groups, has been a point of interest and also of controversy. 310In this letter, by means of Monte Carlo (MC) simulations together with ab initio molecular orbital (MO) method, we shed light on the influence of TMAO on the distribution of the surrounding water and reveal a specific alignment of average dipole moments of solvent water around TMAO. This is the first report concerning the influence of TMAO on the alignment of solvent water molecules.The geometry of TMAO was optimized in the gas phase using the ab initio MO method. The MP2/6-31G* level of theory was used for the geometry optimization using the Gaussian09 program package.11 By means of the normal mode analysis, we confirmed that it is the local minimum structure. TMAO has C 3v symmetry ( Figure 1a). For geometrical parameters, see Table S1 in the Supporting Information.12 The barrier height of one methyl group rotation is +5.2 kcal mol ¹1, indicating that the methyl groups of TMAO are not free to rotate.With the global minimum geometry, the atomic charges of TMAO using natural population analysis (NPA) 13 were calculated: they are listed in Figure 1b. We adapted NPA, since it is generally accepted that NPA gives reasonable values for atomic charges.14 The top-, side-, and bottom-views of the electrostatic potential map of TMAO are shown in Figure 1c. Based on the isoelectronic density surface, we can estimate the effective size of TMAO, which may correspond to the van der Waals volume. Assuming TMAO to be a sphere, the effective radius of TMAO was roughly estimated to be µ3 ¡ with the nitrogen atom as the center. This is a highly polarized spherical polyhedron. It is divided into two parts: one is the partially negative region (oxide region), and the other is the partially positive region (methyl region). The dipole moment of TMAO was calculated to be 4.67 D. This is large, indicating the ability of TMAO to influence the distribution of the ...

A current perspective on the compensatory effects of urea and methylamine on protein stability and function

“…Molecular dynamics simulation (MDS) studies carried out to monitor the effect of urea and TMAO on the structure and dynamics of aqueous solutions have shown that TMAO influences the distribution and alignment of water (Wei et al, 2010;Zou et al, 2002) (by strengthening the life time and strength of the water-water hydrogen bonds) and significantly slows the orientational relaxation of water, but urea has opposite effects on the hydrogen-bonding network (Doi et al, 2014;Larini and Shea, 2013). Therefore, TMAO enhances the tetrahedral water structure while urea decreases the same (Wei et al, 2010).…”

Using a FRET Library with Multiple Probe Pairs To Drive Monte Carlo Simulations of α-Synuclein

“…Solution studies of TMAO have revealed that the large 4.67 D dipole moment prompts significant water ordering around each molecule (35). Comprised of a total of $13 water molecules, direct coordination of water to the oxygen along with formation of a clathrate like structure about the methyl groups produces a first solvation shell with a 6 Å radius, and elicits an excluded volume effect that entropically drives protein compaction (28,(35)(36)(37). In addition to the effects of excluded volume and water arrangement, TMAO has been proposed to act as a nanocrowder and also serves as a poor solvent of the peptide backbone (38,39).…”

Is dynamic heterogeneity of water in presence of a protein denaturing agent different from that in presence of a protein stabilizer? A molecular dynamics simulation study

“…Tetramethylurea (TMU), another amphiphilic molecule, acts as a protein destabilizer, and is a stronger denaturant than urea. 5,6 Interestingly, these two molecules are of similar size (r T MAO ∼3 Å and r T MU ∼3.5 Å, r being van der Waals radius) 9,10 although TMAO possesses a zwitterion structure while TMU is a dipolar amphiphile (Scheme 1). Because of this difference in chemical nature, TMAO is a solid at room temperature whereas TMU is a liquid.…”