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Amino Acid Capture by Aqueous Interfaces. Implications for Biological Uptake Marilia T. C. Martins-Costa†,‡ and Manuel F. Ruiz-Lopez*,†,‡ †

SRSMC, UMR 7565, University of Lorraine, BP 70239, 54506, Vandoeuvre-les-Nancy, France SRSMC, UMR 7565, CNRS, BP 70239, 54506, Vandoeuvre-les-Nancy, France

‡

S Supporting Information *

ABSTRACT: The interactions of natural amino acids with water−hydrophobic interfaces are central to the control of key biological processes, such as passive transport, and to the overall structure and stability of membrane proteins. We still have a very poor knowledge of these interactions, and our aim in this work is to investigate the thermochemistry and dynamics properties of simple aliphatic amino acids (glycine and valine) across a water−organic interface. The study has been carried out by means of Born−Oppenheimer molecular dynamics simulations focusing on the role that the hydrophobicity of the side chain has on the phase transfer mechanism of the amino acid. Data for the energetics of the uptake processes have been reported, and it is expected that the reported results will be helpful in the design of future experiments with systems of biological relevance. We have shown that neutral tautomers exhibit a noticeable affinity for the interface that increases with increasing hydrophobicity of the side chain. Moreover, the zwitterionic form of valine (but not that of glycine) does also exhibit a significant affinity for the interface. An important finding is that the neutral and zwitterionic tautomers are roughly isoergonic in the organic layer close to the interface. This result suggests a two-step mechanism for the water-to-organic phase transfer that involves neutralization of a partially hydrated zwitterion in the organic layer prior to uptake into the bulk. Though the mechanisms for glycine and valine are similar, the predicted energetics and dynamics for the first step display noteworthy differences that should be measurable and may have important biological implications.

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INTRODUCTION The role of water−hydrophobic interfaces on atmospheric, environmental, and biological chemistry is a poorly understood, but potentially very important, topic. On the one hand, it is now widely recognized that many polar molecules and ions are stabilized at the air−water or water−organic interfaces (see ref 1 and references therein) as a result of a subtle combination of electrostatic-polarization and entropic effects. On the other hand, interfacial solvation should modify the molecular properties and the reactivity of the adsorbed solute, but in contrast to solvation in bulk phase, prediction of such effects is not straightforward, even qualitatively. The traditional view of solvation at the interface is quite simple: it assumes that solvation effects are roughly intermediate between the two bulk phases. This intuitive idea has been supported by studies on solvatochromic compounds at the interface using second-harmonic generation spectroscopy that have led to the definition of a generalized interfacial polarity scale.2,3 Accordingly, the polarity of a liquid interface is the arithmetic average of the polarity of the two constituent bulk phases (for instance, the effective polarity of the air/water interface should be close to that of bulk butyl ether3). However, there is now compelling evidence that chemistry at the interface can be quite different from chemistry in the two bulk phases.4,5 Indeed, recent elaborated SFG (sum-frequency generation) experiments6 support the fact that similar molecules can undergo different polarization at the interface depending on © 2013 American Chemical Society

their relative orientation with respect to the plane of the surface. This finding has been further supported by numerical simulations carried out by us,5,7 according to which the reaction field potential created by the polarized interface may be significantly larger (in absolute value) than the potential created by the bulk solvents and its sign depends on the H-bonding donor or acceptor character of the solute. Hence, the active molecular orbitals of species adsorbed at the interface (the HOMO and LUMO, in particular) may be either stabilized or destabilized with respect to the two bulk phases, leading to interface-enhanced or interface-inhibited chemical or photochemical reactions, as schematized in Figure 1. The study of interface solvation effects is, on the other hand, a crucial step to understanding the physicochemical mechanisms involved in phase transfer molecular processes. Such mechanisms have biological relevance because water−hydrophobic interfaces represent a suitable and simple model that allows getting useful insights on how cell membranes work. Passive diffusion of amino acids,8,9 despite its secondary role when compared to assisted transport by carrier proteins, is an emblematic example. This question has stimulated experimental research on the permeability properties of the lipid bilayer10,11 for establishing the background levels of amino acid transport Received: August 21, 2013 Revised: September 18, 2013 Published: September 18, 2013 12469

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Article

METHODS

Molecular Dynamics Simulations. They were carried out in the NVT ensemble at T = 298 K using the Nosé−Hoover thermostat.33,34 The system was composed of one amino acid molecule, 1000 water molecules, and 220 CCl4 molecules. We assumed a combined quantum mechanics and molecular mechanics (QM/MM) force field in the Born−Oppenheimer approximation. The amino acid molecule (the solute) was described quantum mechanically at the density functional theory level, whereas solvent molecules were described using a classical force field. The method allows for electrostatic embedding; that is, the Hamiltonian of the solute includes the electrostatic interaction with the charges of the solvent molecules that were described using the force field proposed before for the H2O/CCl4 interface.35 Specifically, for water, we employed the flexible SPC force field.36 For the calculation of solute−solvent nonelectrostatic interactions, the van der Waals parameters for the QM atoms were taken from the OPLS force field.37 The box size is 24 Å × 24 Å × 114 Å corresponding to densities of 1.00 and 1.57 for water and CCl4, respectively. We apply periodic boundary conditions in the three directions. A cutoff of 12 Å was used for the interactions of both QM and MM systems with their environment. The time step was 0.5 fs. After equilibration, the width of the organic slab is approximately 64 Å. We assumed a neutral pH in water (which is close to the isoelectric point of Gly and Val) so that the amino acids bear no net charge. The simulations were done using Gaussian 0338 for the QM calculations, TINKER39 for the MD simulations, and the program developed by us.40 Free Energy Calculations. Free energy has been calculated using the umbrella sampling41 and WHAM42,43 methods together with the dual level approach proposed recently.44 In this approach, the umbrella sampling is obtained from QM/ MM MD simulations using a low-level QM method (Hartree− Fock, 3-21G basis set). Free energy perturbation theory is then used to obtain the free energy profile at the B3LYP/6-31G(d) level. The reaction coordinate R is taken as the distance between the center of mass of the solute and the center of mass of the organic solvent. The reaction coordinate was varied by steps of 0.25 Å, and the bias potential force constant is k = 10 kcal/mol/Å2. After thermalization, the trajectory was carried out for 50 ps at each point of the reaction coordinate.

Figure 1. Scheme illustrating the interaction of two molecules AH (a proton donor) and BX (a proton acceptor) with a water−hydrophobic interface. The molecular orbitals of the former are destabilized, while the molecular orbitals of the latter are stabilized. Hence, the properties of a hypothetical AH + BX reaction at the interface can be quite different from either bulk phase.5,7

allowed by the membrane and for discussing solute permeation in natural situations prior to the evolution of transport proteins (or where transport proteins are absent). The mechanism of transfer is, however, difficult to unravel10,11 because amino acids exist mainly as zwitterions in aqueous environments and because their side chains may contain ionizable groups. Moreover, a full understanding of the transfer process would need to take into account the acido-basic properties of the water surface, which is still a subject of controversy (see, for instance, refs 12−22), although recent experimental work23 has supported the original prediction12 of hydronium somewhat favoring the water surface. Some theoretical investigations have been devoted to study the phase transfer of natural amino acids. Most of them have focused on their side chains and the uptake into a lipid bilayer24−26 or across the air−water interface,27 which is an important question for understanding the thermodynamics of membrane protein structure and stability.28 Amino acids with N-terminal acetyl and C-terminal N-methyl amide groups at the water−hexane interface were also studied as a model to investigate the effects of the interface on peptide folding.29 In a recent work, we have described the hydration shell of glycine in the vicinity of a water−organic interface,30 whereas other authors have focused on the orientational ordering of asparigine and tryptophan at the air−water interface as well as the proton transfer mechanism in the case of tryptophan.31,32 However, the thermodynamics of amino acid uptake processes has not been established yet, and the aim of the present investigation was to throw some light on this important topic. The present study focuses on aliphatic amino acids, their energetics across water−hydrophobic interfaces, and the mechanism of transfer. It has been carried out using molecular dynamics (MD) simulation techniques developed in our group, which combine quantum chemistry and molecular mechanics methods for describing, respectively, the solute and the solvent. In this way, the possibility for proton transfer between the acid and amino groups of the amino acid induced by the chemical environment is explicitly taken into account. We report and compare free energy profiles for glycine (Gly) and valine (Val) crossing a model water−carbon tetrachloride interface. Finally, we discuss the biological relevance of the results, namely, the possible mechanisms of transfer and the role of hydrophobic side chains.

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RESULTS AND DISCUSSION Amino acids in bulk water exists mainly in ionized form or zwitterions (Zw). In the case of Gly and Val, the relative stability with respect to the nonionized or neutral form has been experimentally (Gly)45 or theoretically (Val)46 determined to be −7.3 kcal/mol. In gas phase and hydrophobic media, only the neutral form is stable. The relative stabilities at water−hydrophobic interfaces are unknown, and estimating these values is one of the goals of our study. Previous works have shown that neutral amino acids may exist in different conformations in gas phase and in solution, and Chart 1 shows the most relevant ones for Gly.47−49 Structures NI and NII are almost isoenergetic, both in the gas phase and in water solution,49 and one may anticipate similar behavior in apolar or low polar media (see below). In water solution, however, the lifetime of NII is too small, as it spontaneously leads to the more stable Zw tautomer (through a very small energy barrier) so that this structure should play a minor role in the measured thermodynamic properties.50 12470

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algebraic value) going from the aqueous to the organic phase. Thus, from the value of −7.3 kcal/mol in bulk water, it reaches −2 kcal/mol at R = 0 (the formal interface) and becomes zero at about R = −2 Å, in the organic layer. ΔGZw,N continues to increase as Gly goes into the organic phase and reaches a maximum of 16 kcal/mol at R = −9 Å, that is, in the region where Zw spontaneously neutralizes. The tautomer molar fraction corresponding to the equilibrium distribution at the neighborhood of the interface would be given by the curves drawn in Figure 3, where we have used the calculated ΔGZw,N

Chart 1

Accordingly, in the following, we will center our attention on the NI tautomer, although we will come back to the role of NII later. The calculated free energy profiles for the Zw and NI tautomers of Gly across the water−hydrophobic interface are represented in Figure 2. In this and the following figures, positive values of R refer to positions in the water layer, whereas negative values refer to locations in the organic layer. The hachured regions correspond to the organic and water layers where solvation is different from solvation in the two bulk phases. Addition of these two layers provides a definition for the total width of the interface, which amounts to about 10−12 Å. Note, however, that the organic layer is broader than the water layer owing to the fact that, when the polar solute is in the organic phase and sufficiently close to the interface, some water molecules create an interface defect that provides a bridge for connecting the solute to bulk water.28,30 As shown in Figure 2, the free energy profile of the neutral form NI exhibits a significant minimum at the interface lying at −1.6 kcal/mol with respect to bulk water. The estimated free energy of transfer of this tautomer from bulk water to bulk CCl4 is 6.4 kcal/mol. The free energy profile of the Zw form, in contrast, does not present any minimum at the interface but increases progressively in going from the aqueous to the organic phase. The calculations also show that Zw becomes unstable in the organic layer at distances from the interface larger than 8−9 Å. In fact, beyond that distance, spontaneous intramolecular proton transfer occurs and the neutral tautomer is formed. The relative stability of the two major Gly tautomers ΔGZw,N = G(Zw) − G(NI) as a function of the distance to the interface is also represented in Figure 2. To obtain this curve, we have combined together the calculated Zw and NI free energy profiles and the experimental tautomerization free energy in bulk water (7.3 kcal/mol). ΔGZw,N, rises regularly (in

Figure 3. Hypothetical equilibrium distribution of Gly tautomers as a function of the distance to the interface obtained using the calculated ΔGZw,N profile in Figure 2.

values and we have neglected the role of neutral conformations other than NI. Coexistence of the two tautomers is predicted in a thin region of the organic layer close to the interface for −4 < R < 0, where the hydration shells surrounding the amino acid are incomplete and the two tautomers Zw and NI become roughly isoergonic; the predicted 50% molar fraction occurs at R = −2 Å. Further free energy calculations for NII have allowed us to show that this tautomer is close in energy to NI, and, therefore, to Zw in the interfacial region. Moreover, the simulations show that NII becomes metastable at around R = −2 Å where it spontaneously evolves to other neutral conformers or to the Zw tautomer.

Figure 2. Calculated free energy profiles for Gly tautomers as a function of the distance to the interface. The red and blue lines represent the free energy of the tautomers (Zw and NI, respectively) relative to bulk water. The black line (full circles) represents the free energy difference of the tautomers ΔGZw,N = G(Zw) − G(NI) (the experimental value is assumed in bulk water). 12471

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Let us now analyze the case of Val. This amino acid bears a hydrophobic side chain (isopropyl), and therefore, the comparison with Gly will allow getting further knowledge on the uptake mechanisms. The free energy profiles for ionized and nonionized Val are depicted in Figure 4 (to limit the

Figure 5. Comparison of the angular distribution of the amino acids Gly and Val at the water/CCl4 interface. The black line represents a regular distribution. The distribution refers to the angle formed by the axis perpendicular to the interface, and the molecular axis defined by the vector bisecting the Ccarboxylic−Calpha−N bond angle; 180° corresponds to polar groups oriented toward the water. Figure 4. Calculated free energy profiles for Val tautomers as a function of the distance to the interface. The red and blue lines represent the free energy of the tautomers (Zw and NI, respectively) relative to bulk water. The black line (full circles) represents the free energy difference of the tautomers ΔGZw,N = G(Zw) − G(NI) (the value calculated by Stover et al46 in bulk water is assumed here).

computational cost, we have focused here on the −7 Å < R < 9 Å region). For the nonionized form, we have chosen a conformation similar to NI in Gly. The free energy profiles for Val present noticeable differences with respect to Gly. First, in this case, we predict free energy minima at the interface for both, the neutral and the ionized forms of the amino acid, with well depths of −5.3 and −1.5 kcal/mol, respectively. From these results, one may conclude that Val will tend to accumulate at water/hydrophobic interfaces, in consistency with its amphiphilic character. Using a previous calculation for the tautomerization free energy of Val in solution (which leads to 7.3 kcal/mol46), we have obtained the ΔGZw,N profile for this amino acid (Figure 4). As shown, the shape of the curve is similar to that obtained for Gly, in particular, ΔGZw,N = −2.8 kcal/mol at R = 0 and ΔGZw,N = 0 kcal/mol at R ≈ −2 Å. However, the maximum value reached when the Zw form neutralizes is 10.1 kcal/mol, much smaller than that for Gly (16 kcal/mol). Likewise, the free energy required for the transfer of Val from bulk water to the organic phase is estimated to 10.0 kcal/mol, instead of 13.8 kcal/mol for Gly (it should be noticed that the tautomerization energy of Val in water estimated by Stover et al46 is probably underestimated, as these authors calculated a value of 6.3 kcal/mol for Gly, which is 1.5 kcal/mol smaller than the experimental measure). Beyond the differences in free energy, an important distinction between Gly and Val comes from their relative orientation with respect to the interface plane. Figure 5 illustrates this point in the case of the zwitterions. Both amino acids exhibit a preference for an orientation in which the polar groups are oriented toward the water solvent; the snapshot in Figure 6 displays a typical arrangement. However, the orientational preference is much more pronounced in the case of Val due to its higher amphiphilic character. This result corroborates similar predictions for the aromatic amino acid tryptophan.31,32 According to the comments made in the

Figure 6. Snapshot of the zwitterionic Val simulation at the water/ CCl4 interface illustrating the preferred orientation of the amino acid (Val carbon atoms are drawn in yellow).

introduction and the work of Sen et al.,6 this orientational preference could influence other physicochemical properties of the amino acid since different polarization effects are expected for different orientations. All of these results put together allow us to formulate the following two-step mechanism for the amino acid transfer slow

(Zw)aq ⇄ (Zw, NI)OLI ⎯⎯⎯→ (NI)organic

(1)

where OLI holds for the thin organic layer close to the interface (−4 < R < 0) in which the major amino acid tautomers display similar stabilities and may coexist. The first step involves the adsorption of the zwitterion at the interface and its neutralization in the OLI. The second step corresponds to the uptake of the neutral tautomer into the bulk organic phase. Figure 7 compares the associated free energy profiles for Gly and Val. They have been obtained by combining the zwitterion and neutral tautomers free energy profiles in Figures 2 and 4, and by assuming that the two tautomers are exactly isoergonic at R = −2 Å, as mentioned above. The figure reveals a major difference between the two amino acids: the transfer of Val from bulk water to the OLI appears to be much less energy demanding than the transfer of Gly. Thus, taking R = −2 Å as the reference point, the transfer energy is 1.9 kcal/mol for Val 12472

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10.0 kcal/mol for Gly and Val, respectively. The easier transfer of valine with respect to glycine is obviously due to the higher hydrophobicity of its side chain, but the simulations demonstrate its decisive role in facilitating the adsorption at the interface during the first step of the uptake process.

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ASSOCIATED CONTENT

S Supporting Information *

Complete ref 19. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Figure 7. Schematic mechanism and calculated free energy profiles for Gly and Val uptake processes. OLI stands for the organic layer close to the interface (−4 < R < 0) where neutralization of the zwitterions occurs.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the French ANR (09-BLAN-018001), the CNRS, and the University of Lorraine. The authors thank the French computational facility CINES (project lct2550).

and 7.0 kcal/mol for Gly. In contrast, in the second step of the process, the uptake into the bulk organic phase from the OLI, the energetics are similar for the two amino acids: about 8 kcal/ mol for Val and 7 kcal/mol for Gly (see Figure 7; the curves for Val and Gly are roughly parallel in the region −8 Å < R < −2 Å). Overall, a lower energy is required for the water-to-organic phase transfer in the case of the amphiphilic amino acid Val by roughly 4 kcal/mol. Finally, one might wonder how the mechanism in eq 1 would compare with the alternative process: neutralization in the bulk aqueous phase, followed by phase transfer of the neutral form. Actually, the experimentally determined free energy of activation for the neutralization process of glycine in bulk water at 298 K is quite large, 14.6 kcal/mol,51 and the activation energy for the corresponding backward process can be deduced to be about only 7 kcal/mol.50 In other words, the neutral tautomer should not survive long enough to reach the interface and the kinetics of the overall phase transfer process should be controlled by diffusion of the amino acid across the interface. The intramolecular proton transfer will readily take place in the OLI induced by the lower polarity of the environment.

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ABBREVIATIONS Gly, glycine; Val, valine; MD, molecular dynamics; QM/MM, quantum mechanics and molecular mechanics; OLI, organic layer close to the interface

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REFERENCES

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CONCLUSIONS In the past, the understanding of amino acid uptake mechanisms has been limited by the lack of experimental thermochemical data. In this study, an elaborated theoretical approach has allowed us to obtain, for the first time, a detailed free energy scheme for the water-to-organic phase transfer of the aliphatic amino acids Gly and Val and to analyze the role of the hydrophobicity of the side chain. In the energetics calculations, two major results have been obtained. First, it has been shown that the neutral and zwitterionic tautomers of both Gly and Val become almost isoergonic in the organic layer close to the interface (OLI), where solute hydration is strongly reduced with respect to bulk water. Second, the simulations confirm the existence of free energy minima at the interface for the neutral forms, and also for the zwitterionic form in the case of Val. Using these data, a two-step uptake mechanism has been proposed consisting of the adsorption−neutralization of the zwitterion at the OLI, followed by the uptake of the nonionized form into the organic phase. Overall, the calculated free energies of water-to-organic phase transfer amount to 13.8 and 12473

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dx.doi.org/10.1021/jp4083689 | J. Phys. Chem. B 2013, 117, 12469−12474