Article pubs.acs.org/Langmuir
Trimethylamine N‑Oxide (TMAO) and tert-Butyl Alcohol (TBA) at Hydrophobic Interfaces: Insights from Molecular Dynamics Simulations Andrew Fiore, Vasudevan Venkateshwaran, and Shekhar Garde* The Howard P. Isermann Department of Chemical and Biological Engineering and The Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States ABSTRACT: TMAO, a potent osmolyte, and TBA, a denaturant, have similar molecular architecture but somewhat different chemistry. We employ extensive molecular dynamics simulations to quantify their behavior at vapor−water and octane−water interfaces. We show that interfacial structuredensity and orientationand their dependence on solution concentration are markedly different for the two molecules. TMAO molecules are moderately surface active and adopt orientations with their N−O vector approximately parallel to the aqueous interface. That is, not all methyl groups of TMAO at the interface point away from the water phase. In contrast, TBA molecules act as molecular amphiphiles, are highly surface active, and, at low concentrations, adopt orientations with their methyl groups pointing away and the C−O vector pointing directly into water. The behavior of TMAO at aqueous interfaces is only weakly dependent on its solution concentration, whereas that of TBA depends strongly on concentration. We show that this concentration dependence arises from their different hydrogen bonding capabilitiesTMAO can only accept hydrogen bonds from water, whereas TBA can accept (donate) hydrogen bonds from (to) water or other TBA molecules. The ability to self-associate, particularly visible in TBA molecules in the interfacial layer, allows them to sample a broad range of orientations at higher concentrations. In light of the role of TMAO and TBA in biomolecular stability, our results provide a reference with which to compare their behavior near biological interfaces. Also, given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions.
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INTRODUCTION
Trimethylamine N-oxide (TMAO) is one of the most potent naturally occurring osmolytes accumulated in the cells of organisms exposed to environmental stresses (e.g., osmotic, hydrostatic). It is known to enhance thermodynamic stability of proteins and protect them against denaturation.1,2 TMAO is also shown to counteract the denaturing action of urea.3 The mechanism of action of TMAO and other osmolytes is thought to be interfacial in naturein the sense that TMAO is thought to be excluded from protein−water interfaces, thus increasing the protein−water interfacial tension and stabilizing more compact folded states of proteins. The physicochemical basis for TMAO exclusion from biological interfaces is a matter of active research.4−7 Like TMAO, the denaturing action of molecules such as tert-butyl alcohol (TBA) is also thought to be interfacial in nature. For example, TBA molecules, like surfactants, are expected to partition favorably at hydrophobic interfaces, solvating hydrophobic residues in the protein core and unfolding proteins. The two molecules TMAO and TBA are of particular interest because their chemical structures are similar to each other (see Figure 1). They both have tetrahedral geometry, with three hydrophobic methyl groups and a fourth hydrophilic group either an oxygen or a hydroxyl, attached to a central nitrogen or carbon atom. Quantifying the behavior of TMAO and TBA molecules at aqueous interfaces at the molecular scale is important to understanding their action. While their behavior at © XXXX American Chemical Society
Figure 1. Chemical structures of TMAO and TBA.
complex protein−water interfaces is of ultimate interest from a biomolecular stability point of view, it turns out that understanding how these molecules behave at simpler flat surfaces with homogeneous chemistry is already a rich problem with potential to provide a wealth of molecular level insights.8,9 To this end, air−water and oil−water interfaces serve as excellent model hydrophobic interfaces.10,11 The surface tension of an air−water interface decreases dramatically upon addition of TBA to water, suggesting that TBA molecules are interfacially active and accumulate there. From the amphiphilic nature of TBA, one would expect the methyl groups of TBA to point toward the hydrophobic phase, away from water. Surface tension of TMAO−water solution decreases somewhat upon addition of TMAO,12,33,34 suggesting Received: March 30, 2013 Revised: May 9, 2013
A
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small accumulation of TMAO at a hydrophobic interface. Molecular dynamics simulations of TMAO at a solid hydrophobic self-assembled monolayer−water interface suggested that TMAO molecules at the interface prefer orientations with their N−O vector parallel to the surface. That is, not all methyl groups of TMAO may be pointed toward the hydrophobic surface.8 Recent experiments using vibrational sum frequency spectroscopy (VSFS) also suggest that the methyl groups of TMAO at hydrophobic−water interfaces are not necessarily pointed toward the hydrophobic phase.9 These recent experimental and simulation studies raise several important questions about the molecular level behaviordensity, orientation, correlations, hydrogen bonding of TMAO, TBA, and waterwhich motivate our molecular dynamics study of these molecules at air−water and octane− water interfaces. Our calculations not only allow us to quantify the extent of accumulation or depletion of TMAO/TBA at air− water and octane−water interfaces, but they also point to the role of the additional van der Waals interactions of the octane phase (relative to vapor) in amplifying the local accumulation. Our simulations show clear differences in the orientational preferences of TMAO and TBA at these hydrophobic interfaces, which originate from the differences in the nature of their hydration, whereas the oxygen atom of TMAO molecule can only accept hydrogen bonds, the hydroxyl group of TBA can both donate and accept hydrogen bonds. The ability to form TBA−TBA hydrogen bonds also makes TBA orientation at the interface sensitive to its concentration, an effect not observed for TMAO. Collectively, our results demonstrate the rich molecular behavior of structurally similar but chemically slightly different molecules at hydrophobic interfaces. We hope that our quantitative predictions of TMAO and TBA behavior at aqueous interfaces will motivate further experimental studies.
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Figure 2. Snapshots of vapor−liquid (left) and octane−water (right) interfacial systems containing TMAO solutes in the water phase. Water (oxygen: red; hydrogen: white) and octane (cyan) molecules are shown in a wire-frame representation. TMAO molecules are shown using space-fill representation (red: oxygen; blue: nitrogen; cyan: carbons; white: hydrogens). The system size is about 4 nm × 4 nm × 10 nm. The snapshots show only a part of the system with focus on the interfacial region.
Table 1. Number of Solute and Solvent Molecules in the Vapor−Water and Octane−Water Systemsa system TMAO
TBA
METHODS
conc (M) 1 2 3 5 1 2 3 5
(0.9) (1.6) (3.1) (5.6) (0.9) (1.7) (3.1) (5.2)
Nsolute
Nwater
Noctane
41 82 173 386 41 82 173 386
2500 2500 2500 2500 2500 2500 2500 2500
280 294 328 402 284 306 380 464
a
In the vapor−water system, Noctane = 0. The exact solute concentrations in our systems are shown in the parentheses. For simplicity, we refer to these concentrations by rounded off integer values, listed in the second column.
Systems. We calculated orientational and structural preferences of TMAO and TBA molecules at (i) water vapor−liquid interface and (ii) octane−water liquid−liquid interface. Figure 2 shows snapshots of both the systems with TMAO as an example. The system is periodic in all three directions, with box dimensions of approximately 4 nm × 4 nm × 10 nm. We placed a ∼4 nm thick water slab at the center of the box, creating two identical vapor−water interfaces. To simulate an octane−water system, the vapor space in the vapor−water system was filled with ∼300−500 octane molecules. The vapor−water and octane−water interfaces are parallel to the xy plane, with the z direction (the longest dimension of the box) being perpendicular to the interface. We studied four different concentrations of TMAO and TBA in solution. Table 1 lists the concentrations and number of osmolyte, water, and octane molecules present in each of these systems. Note that the exact concentrations of species are listed in the parentheses in the table, which for simplicity we refer to in the text with rounded off integers (1, 2, 3, and 5 M). Note also that exact box lengths vary somewhat, especially for different octane−water systems, as they are equilibrated at constant pressure as described in Simulation Details subsection. Force Fields. All molecules were represented explicitly at the atomic level in our simulations. We selected the TMAO, TBA, and water force fields such that their bulk solution behavior is consistent with experiments. The extended simple point charge (SPC/E) model13 was used to represent water. Octane molecules were represented explicitly using bond, angle, and torsion parameters from the AMBER force field.14 Specifically, the carbon atom is of type CT in AMBER; the Lennard-Jones parameters for it are listed in Table 1. For bond length, angle, and torsions, we refer the reader to the AMBER force field paper.14 The Kast model15 was used to represent
TMAO molecules. The parameters to describe TBA were based on the threonine side chain of the AMBER force field,14 with the charges scaled and the excess charge redistributed over all atoms of TBA to achieve neutrality. The nonbonded parameters for the different atom types including their partial charges are listed in Table 2. Simulation Details. Simulations were performed using the molecular dynamics package GROMACS.16 The simulations of vapor−water interfaces were performed in the N,V,T ensemble, equilibrated for 4 ns, followed by a production run of 12 ns. To simulate an octane−water system, the vapor space was filled with octane molecules. The system was then equilibrated for 0.5 ns in the N,V,T ensemble. To obtain box volume corresponding to the pressure of 1 atm, the system was further equilibrated in the N,P,T ensemble using an anisotropic Berendsen barostat17 for 1 ns. Once the system dimensions attained their equilibrium values, we further equilibrated the simulations for 4 ns in the N,V,T ensemble before performing N,V,T production runs of 12 ns. The leapfrog algorithm with a time step of 2 fs was used to integrate the equations of motion. The temperature was maintained at 300 K using the stochastic velocity rescaling thermostat of Bussi et al.18 Electrostatic interactions were calculated using the particle mesh Ewald (PME) algorithm19 with a grid spacing of 0.12 nm and a real-space cutoff of 1.3 nm. The Lennard-Jones interactions were also truncated at 1.3 nm. Parameters for cross-interactions were calculated using the standard Lorentz− B
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profiles of TMAO−nitrogen and water−oxygen near the vapor−water interface for four different concentrations of TMAO in bulk solution. The density values in Figure 3A are normalized by their bulk values and, therefore, highlight the propensity of molecules to accumulate at or deplete from the interface. The corresponding absolute densities of water (O) and TMAO (N) are shown in Figures 3B and 3C, respectively. The density profile of water (in 2 M TMAO solution, in Figure 3A) is sigmoidal in nature and defines the location of the Gibbs dividing surface as z = 0, where the local water density is half of that in the bulk. In fact, water density profiles in all solutions are unremarkable in that they are sigmoidal (Figure 3B), as expected for the vapor−water interface.22 Water density in the bulk decreases with increasing TMAO concentration, as expected. And, only at the highest concentration of TMAO does the water density profile develop a broad peak suggestive of weak layering of water in the interfacial region. We note that TMAO (N) density reaches its bulk value within a distance of ∼1 nm from the interface. Further, we do not observe aggregation of TMAO molecules in the solution even at the highest concentration studied here, consistent with results from the work of Paul and Patey.23 Figures 3A and 3C suggest that TMAO accumulates somewhat at the vapor−water interface, as indicated by the peak of TMAO (N) density located on the liquid side of the vapor−water interface. That the magnitude of surface excess is small suggests only a small decrease in the surface tension of the vapor−water interface upon TMAO addition. Further, the surface excess of TMAO decreases with increasing bulk concentration, in a relative sense, as indicated by the decrease in the height of the peak of the normalized TMAO (N) density (Figure 3A). These data suggest that although the surface tension of TMAO solution will decrease with increasing TMAO concentration, that decrease will be sublinear, saturating at higher concentrations. The extent of surface excess of TMAO observed here is consistent with experimental surface tension changes reported by Kita et al.12 and Auton et al.33 as well as the latest measurements from the Cremer group.34 We note that changes in surface tension upon TMAO addition measured by these experiments are small, approximately 0.5−2 dyn/cm for 2 M solution, indicating only a mild accumulation of TMAO at aqueous vapor−liquid interfaces. Orientation of TMAO at the Vapor−Water Interface. To quantify orientational preferences of TMAO molecules at the interface, we computed the angle θ, made by the N−O bond vector of TMAO with the z-axis, for molecules located in a slab of thickness 0.5 nm centered at the Gibbs dividing surface. Figure 3D shows the probability distribution, P(cos θ), of cosine of the angle θ. The P(cos θ) curve is peaked at θ ≈ 81°, indicating that the dominant orientation of TMAO is one in which the N−O vector is roughly parallel to the vapor−water interface pointing slightly down toward the aqueous phase. These results are consistent with those of Anand et al.,8 who suggested that the N−O vector of TMAO prefers orientations that are parallel to a solid hydrophobic SAM−water interface. They further suggested that the preference for surface parallel orientations is dictated by water−TMAO hydrogen bonds (discussed later in this paper) and the preference of the TMAO oxygen to place itself in the plane of water molecules at the interface. The distribution of θ in their simulations is more sharply defined and peaked at 90°, which is understandable in light of the fact that fluctuations at a solid SAM−water interface are smaller than those at a soft vapor−water interface studied
Table 2. Nonbonded Parameters for TMAO and TBA Atoms TMAO atom
q, e
σ, nm
ε, kJ/mol
C H N O
−0.2600 0.1100 0.4400 −0.6500
0.304 0.178 0.292 0.327
0.2828 0.0774 0.8368 0.6385
TBA q, e
atom
−0.2438 0.3703 0.0691 −0.6761 0.4151 Octane
C (methyl) C (tertiary) H (methyl) O H (hydroxyl)
σ, nm
ε, kJ/mol
0.340 0.340 0.265 0.307 0.000
0.4577 0.4577 0.0657 0.8803 0.0000
atom
q, e
σ, nm
ε, kJ/mol
C H
0.0000 0.0000
0.340 0.265
0.4577 0.0657
Berthelot mixing rules.20 The LINCS21 algorithm was used to constrain the bonds in water molecules. Configurations were stored every 0.5 ps for analysis.
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RESULTS AND DISCUSSION Our MD simulations focused on the behavior of TMAO and TBA at vapor−liquid and octane−water interfaces at ambient conditions. In this section, we first focus on TMAO and TBA at vapor−liquid interface of water, which captures the key differences in their behavior at hydrophobic interfaces. We then discuss the effects of replacing the vapor phase with octane on interfacial structure and orientation of TMAO and TBA. Finally, we discuss and highlight the aspects of hydration and hydrogen bonding of these molecules and connect them with the interfacial orientational preferences. TMAO at the Vapor−Liquid Interface of Water. TMAO Density Profiles. Figure 3A shows atom number density
Figure 3. (A) Normalized density profiles of TMAO nitrogen at the water vapor−liquid interface. Normalized density profile of water in 2 M TMAO solution is also shown for reference. (B) The absolute number density profiles of water oxygen and (C) TMAO nitrogen. (D) The probability distribution of the angle, θ, made by the N−O vector with the z-axis. C
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the tertiary C−O bond vector with the z-axis. There are two notable differences between P(cos θ) distribution for TBA and TMAO. First, at low concentrations, the dominant orientation of TBA molecule is one with θ ≈ 0°, where the C−O vector points directly into the water phase with all methyl groups pointing into the vapor phase. At low concentration of TBA, there is only a small probability of TBA molecules to adopt a surface parallel orientation (the dominant orientation for TMAO) and almost zero probability of TBA pointing its hydroxyl group toward the vapor phase with methyl groups pointing into the water phase. Second, the P(cos θ) profile is sensitive to TBA concentration and flattens significantly at higher concentrations, indicating that many orientations become possible at higher concentrations of TBA. We show later in the paper that this flattening of P(cos θ) results from the ability of TBA molecules to form hydrogen bonds with each other. TMAO and TBA at the Octane−Water Interface. Density Profiles at the Octane−Water Interface. Figure 5
here. Figure 3D shows that the preferred orientation of TMAO molecules at the interface has only a small concentration dependence. At higher concentrations, the dominant angle moves closer to 90°, indicating nearly surface-parallel orientations of TMAO at the interface. TBA at Vapor−Liquid Interface of Water. TBA Density Profiles. Figure 4A shows number density profiles of TBA
Figure 4. (A) Number density profiles of TBA (tertiary carbon) at the water vapor−liquid interface. Number density profile of water (oxygens) is also shown for reference. (B) The probability distribution, P(cos θ), where θ is the angle made by the C−O bond vector with the z-axis. See schematic in the inset.
(tertiary carbon) and water oxygen near the Gibbs dividing surface for four different concentrations of TBA. We show only the absolute densities (TBA on the left and water on the right axis) because the significant surface excess of TBA washes out all other details when normalized density profiles are viewed. The TBA molecules are highly surface active, as indicated by the well-defined peak in absolute density, for example, for the 1 M TBA solution shown in Figure 4A. The location of that peak is slightly to the vapor side of the Gibbs dividing surface, unlike that for TMAO, which prefers the liquid side. As more TBA is added, the concentration at the interface increases, and the location of the peak shifts more toward the vapor side. At the highest concentration studied here, a thick layer of TBA molecules forms at the interface (see Figure 4C) akin to a separate phase. Simulations of Paul and Patey23 have shown that TBA molecules, unlike TMAO molecules, are poorly hydrated and display a tendency to aggregate in TBA−water solutions. Our observation of a thick layer of TBA molecules nucleated by the vapor−water interface at higher concentrations is, thus, consistent with those results. The large surface excess of TBA at the vapor−water interface is also consistent with experimental surface tension measurements, which show that the surface tension drops from ∼72 dyn/cm for pure water to 39.5 dyn/cm for 1 M TBA solution and further to 23.2 dyn/ cm for 5 M TBA solution.24 Orientation of TBA at the Vapor−Water Interface. Similar to what was done for TMAO, we calculated the distribution, P(cos θ), for TBA at the interface, where θ is the angle made by
Figure 5. (A) Normalized density profiles of TMAO nitrogen, water oxygen, and octane carbon are shown. (B) Absolute density profiles of TMAO nitrogen at different TMAO concentration are shown. The water oxygen (black) and octane carbon (dashed gray) densities are shown for reference.
shows density profiles of various constituents in the TMAO− water−octane system at different concentrations of TMAO. The features of the underlying octane−water interface are similar to that reported previously using simulations10 or experiments,22 with sigmoidal density profiles for both water and octane. Much of the density variation in the interfacial region is restricted to about 1 nm thick region near the Gibbs dividing surface. The TMAO density profile is qualitatively similar to that at the vapor−water interface, except that the surface excess of TMAO is amplified, especially at lower concentrations. Preliminary temperature-dependent runs (not shown) suggest that the origin of this amplification is primarily enthalpic in nature. Indeed, the liquid octane phase provides D
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additional van der Waals attractions to TMAO molecules as well as to water, which are absent in the vapor−water interface system. Significant further calculations would be needed, however, to tease out the precise origin of the factors contributing to the observed amplification of the TMAO surface excess at the octane−water interface. The interfacial concentration of TBA molecules is similarly enhanced in the presence of the octane phase (Figure 6A). However, unlike that at the vapor−water interface, at high concentrations, the interfacial layer of TBA remains welldefined, and we observe a clear partitioning of TBA between the water phase, the interface, and the octane phase, as shown in Figures 6A,B.
Figure 7. Orientational preferences of (A) TMAO and (B) TBA at the octane−water interface. See Figures 3 and 4 for definitions of the angle θ for TMAO and TBA, respectively.
Hydrogen Bonding of TMAO and TBA at the Vapor− Water Interface. Figure 8 shows density profiles of TMAO
Figure 6. (A) Density profiles of TBA tertiary carbon, water oxygen, and octane carbon are shown. (B) A snapshot of a part of simulation configuration showing TBA accumulation at the interface and partitioning between the water and octane phases for the 5 M system. Water (red and white) and octane (gray) are shown in stick representation, whereas TBA is shown in space-fill representation (cyan: carbon; white: hydrogen; red: oxygen).
TMAO and TBA Orientations at the Octane−Water Interface. Figure 7A shows that the orientational preferences of TMAO molecules at the octane−water interface are almost identical to that observed at the vapor−liquid interface of water. This is expected given that TMAO−water hydrogen bonds dictate the TMAO orientations8 and that the behavior of water at these two hydrophobic interfaces is known to be similar. 10,11,25 Figure 7B shows that the orientational preferences of TBA at the octane−water interface are also similar to that at the vapor−liquid interface, especially at low concentrations of TBA. At higher concentrations, TBA partitions between the interfacial layer and the bulk of the octane phase, highlighted by smaller width of the interfacial peak in the density profile. As a result, TBA−TBA hydrogenbonding interactions appear to play a less prominent role at the octane−water interface, relative to that at the vapor−water interface, making the orientational preferences only weakly dependent on TBA concentration.
Figure 8. (A) Density profiles of water oxygen (OW) and hydrogen atoms (HW) and TMAO nitrogen (N) and oxygen (O) from the socalled instantaneous interface.26 (B) Same as panel A for the tertiary carbon (C) and oxygen (O) of the TBA system. In panel B, TBA density is on the left scale and water on the right. The profiles presented are for the vapor−water interface at 1 M concentration.
(N and O), TBA (tertiary C and O), and water (O and H) from the so-called instantaneous interface.26 An instantaneous configuration of a vapor−liquid interface is not flat but contains capillary fluctuations. Using the procedure of Willard and Chandler,26 we coarse-grained configurations (with coarsegraining parameters of ξ = 0.28 nm for all heavy atoms in the system, cutoff distance of 3ξ, and the grid spacing for interpolation equal to 0.1 nm) and define the instantaneous interface for each configuration as the locus of points in space E
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with density equal to half of that in the bulk. We then calculated density profiles in each configuration with respect to the instantaneous interface (instead of from the Gibbs dividing surface, which averages over capillary fluctuations).26 Density profiles of water (O and H) in Figure 8A show characteristics of layering, as is expected26the vapor−liquid interface of water is sharp, water molecules layer at such an interface showing an oscillatory density profile near the interface. It is the thermal capillary waves that smooth this profile to a sigmoidal one (as in Figure 3) when viewed with respect to a fixed laboratory frame of reference. Other subtle features, such as the tail of hydrogen density extending a bit more into the vapor side than the oxygen density tail, are consistent with the presence of dangling hydrogen bonds at a vapor−liquid interface of water.27 The first peaks of water oxygen and hydrogen densities occur roughly at the same location, consistent with the fact that water molecules are oriented primarily with their HOH planes parallel to the interface.10,28 Density profiles of TMAO N and O atoms (in 1 M solution) show clear excess and layering with reference to instantaneous interface. TMAO molecules at the interface are located on the liquid side of the interface, with the peak of oxygen slightly to the right of the peak of nitrogen density, suggesting orientations consistent with the θ ≈ 81° peak in Figure 3D (i.e., N−O vector being roughly parallel to the surface but pointing slightly inward to the liquid phase). Also, as observed by Anand et al.,8 the peaks of TMAO (N and O) and the peaks of water (O and H) are in the vicinity of each other, suggesting hydrogen bonding of TMAO with water molecules in the first layer. The water density from the instantaneous interface for TBA solution is qualitatively different from that for TMAO. Water molecules do not layer relative to the instantaneous interface. Instead, only a shoulder is visible in the density profile located to the left of the first peak. This is a result of the significant surface excess of TBA molecules. As shown in the earlier section, TBA molecules are highly interfacially active (note the scale of TBA density) and reside somewhat toward the vapor side of the interface. Thus, there is much less water in the first layer of TBA compared to that for TMAO, leading to the lack of a clear first peak in water density from the instantaneous profile. The orientation of TBA molecules at the interface, with the C−O vector pointing toward the liquid water phase, is clear from the distance of ∼1.4 Å (the C−O bond length) between peaks of densities of tertiary carbon and hydroxyl oxygen of TBA. A TMAO molecule can only accept hydrogen bonds from water. Also, TMAO molecules (in their neutral state, which is what is simulated here) can not directly hydrogen-bond with each other. We define a TMAO to be hydrogen bonded with water if the TMAO (O) and water (O) atoms are within a distance of 0.35 nm of each other (i.e., they are nearest neighbors) and if the angle TMAO (O)−water (O)- and water (H) is less than 30°.29 Panels A, B, and C in Figure 9 show the average number of hydrogen bonds, ⟨NHB⟩, average number of nearest neighbors, ⟨NN⟩, and their ratio, respectively, in the vapor−liquid interfacial region. In bulk water, TMAO (O) has on average 3 nearest-neighbor water molecules, of which about 2.5 are hydrogen-bonded to it. A snapshot of TMAO located at the interface, accepting three hydrogen bonds from water molecules, is shown in the picture on the top left in Figure 8. As TMAO moves toward the vapor−liquid interface, both the nearest neighbors and the number of hydrogen-bonded
Figure 9. Concentration dependence of (A) number of hydrogen bonds, (B) nearest water neighbors, and (C) ratio of hydrogen bonds to nearest neighbors for TMAO in the interfacial region. All hydrogen bonding data are calculated at the vapor−water interface.
neighbors decreases somewhat (∼2.5 and ∼2, respectively, at the Gibbs dividing surface). However, the ratio ⟨NHB⟩/⟨NN⟩ increases as one approaches the interface and especially the vapor side. This observation is consistent with the behavior of hydrogen bonding between water molecules observed at an octane−water interface by Patel et al.10 In the lower dielectric environment of the interface, TMAO (or water) molecules appear to form stronger electrostatic interactions with their neighbors, thus increasing the fraction of nearest neighbors that are hydrogen bonded. These trends are observed for all concentrations with small quantitative changes in the average number of hydrogen bonds and nearest neighbors, consistent with the observation that TMAO structure and orientations at the vapor−liquid interface are not very sensitive to its concentration. Hydrogen bonding of TBA is qualitatively different from that for TMAO for two reasons: first, TBA molecules can accept hydrogen bonds from water molecules as well as donate one to water molecules; second, TBA molecules can form hydrogen bonds with other TBA molecules. Figure 10A shows that in bulk, TBA forms ∼2.4 hydrogen bonds, mostly with water molecules. As TBA moves closer to the interface and to the vapor side, the number of hydrogen bonds with water decreases, but those with other TBA molecules increases (Figure 10). The number of TBA−TBA hydrogen bonds peaks roughly at the location of the density peak of TBA in the interfacial region (Figure 4) and is dependent on TBA concentration. For 1 M solution, average TBA−TBA hydrogen bonds are ∼0.25 (at its peak value in Figure 10C). This number increases to over 1 for the 5 M solution. Analysis of configurations and visual inspection of simulation snapshots points to a number of interesting TBA−TBA hydrogenbonding configurations, some of which are shown in panels D, F
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a clearly defined layer at aqueous interfaces. At low concentrations, TBA molecules adopt orientations with their C−O vector pointing toward the water phase. However, with increasing concentration (and accumulation) of TBA at the interface, TBA−TBA hydrogen bonding also becomes important, allowing TBA molecules to sample a diversity of orientations, thus making their orientations concentration dependent. The differences in density profiles of TMAO and TBA molecules in the interfacial region for vapor−water and octane−water interfaces also point to the role of octane−solute van der Waals interactions, as well as solubility (especially of TBA) in the octane phase. The main results of our simulations are the clear and nonintuitive differences between the behavior of TMAO and TBA molecules at vapor−water and octane−water interfaces. These differences will be of interest to experimental chemical physics community focused on understanding the role of hydrogen bonding and solvation in determining the orientation of molecules at interfaces of water.22,30−32 Aqueous solutions of TBA, water, and organic impurities are also of interest for the mesoscale inhomogeneities formed in such systems.35,36 Behavior of TBA at water−organic impurity interface in those systems may be similar to that observed here. Given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions. Finally, given the role of TMAO and TBA in biomolecular stability, our results provide a reference with which to compare their behavior near biological interfaces.
Figure 10. (A) Number of hydrogen bonds formed by TBA with water and other TBA molecules in the interfacial region for 5 M system. Concentration dependence of (B) number of hydrogen bonds with water and (C) with other TBA molecules. Panels D−F show snapshots of TBA molecules in the interfacial region that illustrate TBA−TBA interactions and hydrogen bonding (see text). All hydrogen-bonding data are calculated at the vapor−water interface.
E, and F of Figure 10. Panel D shows a configuration of one TBA molecule (on the right) donating a hydrogen bond to another TBA molecules (on the left). Panel E shows a configuration in which, although the two TBA molecules are not hydrogen bonded to each other, the dipoles of their OH groups are aligned favorably, comprising two oxygen−hydrogen electrostatic interactions. At the highest concentration, hydrogen-bonded chains of TBA molecules are also observed within the TBA layer (panel F shows seven TBA molecules in a chain). The competition between TBA−water and TBA−TBA interactions explains the observed dependence of orientations of TBA on concentration. At low concentrations, TBA−water hydrogen bonds dominate the interaction, leading to the TBA C−O vector pointing toward the water phase for TBA molecules at the interface. With increasing TBA concentration, however, a layer of TBA molecules forms at the interface (with low concentration of intercalated water in it). In this layer, TBA−TBA hydrogen bonding becomes important, allowing the C−O vector of TBA molecules to sample a broader space of θ values (see configurations shown in panels D−F or Figure 10), thus making the orientational preferences concentration dependent. The hydrogen-bonding preferences at the octane−water interface were qualitatively similar to those at the vapor−water interface for both TMAO and TBA at all concentrations.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (S.G.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS S.G. gratefully acknowledges financial support of NSF-CBET (1159990) grant. We thank Srivathsan Vembanur for helpful discussions.
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REFERENCES
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CONCLUSIONS We presented results from molecular dynamics simulations of TMAO and TBA at two aqueous interfaces (air−water and octane−water). Our simulations highlight differences in structural and orientational preferences of these two molecules with similar architecture but slight differences in chemistry. TMAO molecules are somewhat active interfacially and adopt orientations with their N−O vector being roughly parallel to the aqueous interface. This behavior of TMAO at the interface is only weakly dependent on its solution concentration. In contrast, TBA molecules are highly interfacially active, forming G
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