Large Hydrogen-Bond Mismatch between TMAO and Urea Promotes Their Hydrophobic Association

Xie, Wen Jun; Cha, Sungdeok; Ohto, Tatsuhiko; Mizukami, Wataru; Mao, Yuezhi; Wagner, Manfred; Bonn, Mischa; Hunger, Johannes; Nagata, Yuki

doi:10.1016/j.chempr.2018.08.020

Cited by 35 publications

(62 citation statements)

References 61 publications

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“…The appearance of TMAO at the topmost water layer demonstrates that the methyl group of TMAO is very hydrophobic, which is critical to account for the counteracting effects of TMAO and urea on the protein folding. [41,42] Furthermore, this work suggests that the orientational distribution should be carefully examined to obtain the average angles not only for the O-H stretch mode of water but also for the C=O, N-H and C-H stretch mode. These modes have been frequently used for probing proteins [43,44], a small molecule [45], and lipids [46,47] at the water-air interface as well as the ionic liquid-air interface [48][49][50][51].…”

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confidence: 99%

Orientational Distribution of Free O-H Groups of Interfacial Water is Exponential

et al. 2018

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The orientational distribution of free O-H (O-D) groups at the H 2 O (D 2 O)-air interface is investigated using combined molecular dynamics (MD) simulations and sum-frequency generation (SFG) experiments. The average angle of the free O-H groups, relative to the surface normal, is found to be ~63 o , substantially larger than previous estimates of 30-40⁰. This discrepancy can be traced to erroneously assumed Gaussian/stepwise orientational distributions of free O-H groups. Instead, MD simulation and SFG measurement reveal a broad and exponentially decaying orientational distribution. The broad orientational distribution indicates the presence of the free O-H group pointing down to the bulk. We ascribe the origin of such free O-H groups to the presence of capillary waves on the water surface. Main Text At the interface of water with hydrophobic media, the hydrogen-bond (H-bond) network of water is interrupted, making the O-H groups of the topmost interfacial water molecules dangling (free) from the H-bond network. These free O-H groups are important for determining the energetics of the water surface and are thereby critical for explaining the exceptionally high surface tension of water. Furthermore, free O-H groups provide a unique platform for hydrophobic hydration assembly [1-3], on-water catalysis [4], and growth of aerosol particles [5,6]. As such, there have been many efforts to quantify the number and orientation of free O-H groups at different aqueous interfaces. The free O-H (O-D) groups of interfacial water can be studied experimentally by a sharp peak at ~3700 (~2740) cm-1 in the surface-specific vibrational sum-frequency generation (SFG) spectrum [7-12]. The frequency of the free O-H signal has been examined to determine the interaction strength of the topmost water layer and the hydrophobic medium [13-17]. Moreover, the free O-H SFG response measured with different polarization combinations provides information about their orientation. From the ssp-SFG (shorthand for s, s, and p polarized sum-frequency output, visible input, and infrared input, respectively) and ppp-SFG signals of the free O-H stretch, the averaged angle of the free O-H group at the water-air interface has previously been estimated to 30-40⁰ [17-19]. The orientational distribution of the free O-H group has been concluded to broaden with increasing temperature induced by disordering of the topmost water layer [20,21]. However, to connect the ppp-/ssp-SFG peak amplitudes of the free O-H stretch (A ppp and A ssp , respectively) with the averaged angle of the free O-H group, one needs to assume a functional form for the orientational distribution of the free O-H groups. So far, the distribution has been assumed to be stepwise shaped [18,20,21] or Gaussian shaped [17,19].

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Orientational Distribution of Free O-H Groups of Interfacial Water is Exponential

et al. 2018

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“…S10). Though earlier studies have supported TMAO accepting 3 hydrogen bonds from water (48)(49)(50), a recent study suggests that TMAO can form up to 4 hydrogen bonds with water at high pressure, and we see this effect on a smaller scale in our variable temperature simulations as well (6). The ability of TMAO to form up to four hydrogen bonds with water may be one of the reasons it is able to disrupt water structure and herd more water molecules towards the protein surface, and why the effect quickly saturates with TMAO concentration.…”

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confidence: 96%

TMAO: Protecting Proteins from Feeling the Heat

Boob¹,

Sukenik²,

Gruebele³

et al. 2022

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Osmolytes are ubiquitous in the cell and play an important role in controlling protein stability under stress. The natural osmolyte trimethylamine N-oxide (TMAO) is used by marine animals to counteract the effect of pressure denaturation at large depths. The molecular mechanism of TMAO stabilization against pressure and urea denaturation has been extensively studied, but unlike the case of other osmolytes the ability of TMAO to protect proteins from high temperature has not been quantified. To reveal the effect of TMAO on folded and unfolded protein ensembles and the hydration shell at different temperatures, we study a mutant of the well-characterized, fast-folding model protein B (PRB). We carried out >190 µs in total all-atom simulations of thermal folding/unfolding of PRB at multiple temperatures and concentrations of TMAO. The simulations show increased thermal stability of PRB in presence of TMAO. Partly structured, compact ensembles are favored over the unfolded state. TMAO forms two shells near the protein: an outer shell away from the protein surface alters hydrogen bond lifetimes of water molecules and increases hydration of the protein to help stabilize it; a less-populated inner shell with opposite TMAO orientation closer to the protein surface binds exclusively to basic side chains. The cooperative co-solute effect of the inner and outer shell TMAO has a small number of TMAO molecules ‘herding’ water molecules into two hydration shells at or near the protein surface. The stabilizing effect of TMAO on our protein saturates at 1 M despite higher TMAO solubility, so there may be little evolutionary pressure for extremophiles to produce higher intracellular TMAO concentrations if true in general.

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“…5-7, 10, 11, 13 Ab initio molecular dynamics (AIMD) simulations are essential for explaining the experimental results precisely, because of the fluctuating polarization interactions in the aggregated systems. Although there have been several sub-picosecond-order AIMD simulations, [15][16][17][18][19][20] there have been no nanosecond-order AIMD simulations while reproducing the TMAO concentration and diffusion coefficients of water in deep-sea fishes.…”

Section: Introductionmentioning

confidence: 99%

Electronic fluctuation in physiological solutions: Trimethylamine N-oxide and tert-butyl alcohol

Kuroki

Uchino

Funakura

et al. 2022

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Although small organic molecules in cells have been considered important to control the functions of proteins, their electronic fluctuation under real physiological conditions has never been clarified due to the lack of observations. Herein, the time evolutions of the interactions in dilute aqueous trimethylamine N-oxide (TMAO) and tert-butyl alcohol (TBA) solutions were analyzed via ab initio molecular dynamics simulations accelerated with the fragment molecular theory. It has been known that TMAO and TBA have similar structures, but opposite physiological functions to stabilize and destabilize proteins. It was clarified that water dipole in the TMAO solutions are up to 1.5 times enhanced that affect protein stabilization. Understanding the solution dynamics will contribute to artificial chaperone design in next generation medicine.

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Large Hydrogen-Bond Mismatch between TMAO and Urea Promotes Their Hydrophobic Association

Abstract: Ziel ist hierbei, Medikamente zu entwickeln, die selektiv von bestimmten Zelltypen aufgenommen werden und in diesen Zellen dann krankhafte Prozesse spezifisch stoppen.

Cited by 35 publications

References 61 publications

Orientational Distribution of Free O-H Groups of Interfacial Water is Exponential

Orientational Distribution of Free O-H Groups of Interfacial Water is Exponential

TMAO: Protecting Proteins from Feeling the Heat

Electronic fluctuation in physiological solutions: Trimethylamine N-oxide and tert-butyl alcohol

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