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Reverse Stability of Oxyluciferin Isomers in Aqueous Solutions Yoshifumi Noguchi, Miyabi Hiyama, Motoyuki Shiga, Osamu Sugino, and Hidefumi Akiyama J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b04963 • Publication Date (Web): 01 Aug 2016 Downloaded from http://pubs.acs.org on August 12, 2016

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The Journal of Physical Chemistry

Reverse Stability of Oxyluciferin Isomers in Aqueous Solutions Yoshifumi Noguchi,∗,† Miyabi Hiyama,† Motoyuki Shiga,‡ Osamu Sugino,† and Hidefumi Akiyama† †Institute for Solid State Physics, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8581, Japan ‡Center for Computational Science and E-Systems, Japan Atomic Energy Agency 148-4 Kashiwanoha Campus, 178-4 Wakashiba, Kashiwa, Chiba, 277-0871, Japan E-mail: [email protected] Phone: +81 (4)7136 3291. Fax: +81 (4)7136 3443

Abstract We investigated the stability of oxyluciferin anions (keto, enol, and enolate isomers) in aqueous solution at room temperature by performing a nanosecond timescale first-principles molecular dynamics simulation. In contrast to all previous quantum chemistry calculations which suggested the keto-type to be the most stable, we show that enol-type is slightly more stable than the keto-type in agreement with some recent experimental studies. The simulation highlights the remarkable hydrophobicity of the keto-type by the cavity formed at the oxyluciferin-water interface as well as a reduction in hydrophobicity with the number of hydrating water molecules. It is therefore predicted that the isomeric form in a hydrated cluster is size-dependent.

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INTRODUCTION The oxyluciferin anion plays a key role in firefly bioluminescence as a light emitter in watercontained luciferase. One of the basic issues in understanding the bioluminescence mechanism is to identify the molecular structure of oxylyciferin anion, either in keto-, enol-, and enolate- isomeric forms, in aqueous environments. 1 Since the 1950s, although many studies have investigated their stability, 2–13 their stability order remains debatable. 11–24 Recent studies suggest that the stability is extremely sensitive to molecular arrengement such as isolated, complex, or crystal phases, and external factors such as the pH, and thus, the keto-, enol-, and enolate-types are all possible candidates for the light emitter. 11–21,25–35 These reports have also indicated the difficulty in finding a key factor determining the stabilities of oxyluciferin isomers from only the experimental side, because the experimental condition is already affected by multiple external environmental factors. As a result, theoretical studies as well as combined theoretical and experimental studies of this problem are gaining increasing importance. So far, first-principles simulations have not been done on the oxyluciferin isomers under an explicit solution condition, but mostly done on the isolated isomers or the isomers surrounded by a continuum model solution with or without a few explicit water molecules. The previous simulations have consistently suggested that the isolated keto-type oxyluciferin monomer is the most stable not only in the vacuum but also in a dielectric continuum (Fig. 1); 36 however, such coexistence of other isomers is unlikely. 23,37,38 It should be noted that this result is unaffected even when the oxyluciferin is bound to a protein, as shown by a recent QM-MM molecular dynamics simulation. 24 In this context, it is important to reexamine the hydration effect beyond the dielectric continuum model. The hydration effect has been studied in detail in organic chemistry 39–43 and has revealed unexpected hydration structures; 44–48 this may have a bearing in our study, although the hydration energy of small molecules is often explained locally in terms of contacting water molecules. 24,42,43 However, the hydration effect should be determined nonlocally in terms of the detailed balance of surface/interface energies or the balance of surface 2


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Figure 1: Stabilities of oxyluciferin isomers in vacuum (left) and in the PCM soluvation model (right).

tensions, as illustrated in the old theory of wetting. 49 The non-local hydration effect, if it exists, may be straightforwardly and clearly examined by incorporating all important water molecules into a molecular simulation, although doing so would be very time-consuming. In this light, the aim of our study is to do such simulation to obtain a satisfactory insight into the ground state of oxyluciferin anions in neutral water solution. We performed a first-principles molecular dynamics (FPMD) simulation of keto-, enol-, and enolate-type oxyluciferin anions. Despite the slow relaxation of the surrounding water molecules, which tends to hamper the application of FPMD, modern computers have made it practical to simulate the relaxation for 1 ns, which is sufficient for the system to be in thermal equilibrium. The simulation result is then compared with additional static calculations in which oxyluciferin is surrounded by a number of water molecules arranged in an optimized geometry. From these simulations, we show that the non-local hydration effect plays an important role.

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RESULTS AND DISCUSSION Oxyluciferin in water cluster with PCM First, we investigate how water molecules surrounding an oxyluciferin anion would show a relaxed structure. Then, we present the result of the FPMD simulation. Geometry optimization was performed to characterize the quenched hydration structure. Hereafter, we abbreviate keto-, enol-, and enolate-type oxyluciferin anions as keto, enol, and enolate, respectively, and the oxyluciferin anion as oxyluciferin.

Figure 2: Hydration structure of keto (upper panels) and the total energy of enol and enolate referred to that of keto (lower panel).

The calculation was performed using water molecules, (H2 O)n (n = 0, 8, 11, 20, 30, 50, and 64), surrounding oxyluciferin and a polarizable continuum model (PCM) 50,51 that wraps the water molecules; note that n = 0 corresponds to the conventional PCM calculation that predicts that keto is more stable than other isomers by 0.4–0.5 eV (Fig. 1). After relaxing 4


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the geometry from the randomly arranged initial water configurations, the total energy was obtained (Fig. 2). The details of the cluster model calculation are provided in Supporting Information. The energy referred to that of keto is positive for enol and enolate when the number of water molecules is less than 50, indicating that enol and enolate are less stable than keto unless surrounded by a sufficiently large number of water molecules. For example, when surrounded by 64 water molecules, enol and enolate are more stable than keto by 0.26 and 0.13 eV, respectively. This result indicates that the hydration energy of the water cluster cannot be reproduced by simply replacing the water molecules by the dielectric continuum model. This result of the hydration energy is examined further in the next section by incorporating finite temperature effects.

Figure 3: Charge populated in benzothiazole (C7 NS) part and that populated in thiazole (C3 NS) part as obtained from a natural population analysis.

Next, we focus on the hydration structure of the cluster model. Oxyluciferin consists of benzothiazole (C7 NS) and thiazole (C3 NS) parts (Fig. 3), in which O and N atoms have a 5



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hydrophilic nature compared with C and S atoms. Accordingly, water molecules are arranged in contact with O and N atoms when the cluster size n is small (Fig. 2). With increasing n, water molecules are arranged around C and S atoms as well. However, they are located away from the bottom side when (n ≤ 30), as shown in Fig. 2, suggesting that the bottom side has a more hydrophobic nature. The bottom side is finally wrapped by water molecules at n = 64. All isomers show similar wrapping behavior; however, the repulsion of water by the bottom side is apparent only in keto, possibly reflecting the more hydrophobic nature of keto at this side. This result is consistent with the fact that keto loses stability significantly at n = 64 when water surrounds all sides. The different hydrophobicity of each isomer can be explained at least partially by the distribution of the excess charge within the oxyluciferin anion. The amount of charge distributed in the benzothiazole and thiazole parts is shown in Fig. 3, which shows a common tendency that benzothiazole is more negatively charged than thiazole. This result indicates that benzothiazole can potentially attract more water molecules. Importantly, the absolute amount of charge is the smallest for keto, indicating that keto is closer to charge neutral than the other isomers. This suggests that keto has intrinsically stronger hydrophobicity.

Stabilities in aqueous solution Now, we discuss the result of the FPMD simulations performed for oxyluciferin and 64 surrounding water molecules by applying the periodic boundary condition. For accurate and reliable discussion, we have run FPMD up to 1 ns, corresponding to over 2 million MD steps; this takes around 200 days when using 128 Intel Xeon processors for each isomer. In the simulation, the internal energy showed convergence in around 0.7 ns with 0.1 eV error according to our block average analysis; a subsequent simulation of 0.3 ns duration was used to take an average. For further details, see Supporting Information. The cumulative average of the internal energy (Fig. 4) shows that enol is the most stable whereas others are less stable by 0.20–0.25 eV. The result is qualitatively different from 6


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Figure 4: Time evolution of the cumulative average internal energy.

those obtained by PCM (see Fig. 1), indicating that the hydration effect not described by the dielectric continuum model plays a significant role. By comparing the internal energy with the total energy of oxyluciferin isolated in vacuum (shown in Fig. 1), we found that the energy gained by hydration is smaller for keto than that for others by 0.7–0.8 eV, which is a remarkably large difference.

Distribution of water molecules Now, we analyze the simulation in more detail to find a reason for the loss in stability for keto. By carefully monitoring the trajectory of the FPMD simulations, we find that the distribution of water molecules is different among the isomers; in addition, the distribution is qualitatively different from the optimized geometry obtained by the cluster model calculation, as shown in Fig. 2. Typical snapshots of the FPMD, shown in Fig. 5, indicate that oxyluciferin is hydrogen bonded to nearby water molecules that form hydrogen bond networks surrounding oxyluciferin. This situation corresponds to a formation hydration shell or, possibly, the formation of a water wire. 44–48 For keto, the hydration shell is not formed at the bottom

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Figure 5: Snapshot of the first-principles molecular dynamics simulation. Only those water molecules in contact with oxyluciferin are shown. For keto, there is a region where water is not populated, which is indicated in green.

side, which has a hydrophobic nature; instead, a cavity is formed where no water molecules exist, as indicated in green in Fig. 5. (See Supporting Information for details; the remarkably poor water population in the cavity can be confirmed from the movies). In contrast, for enol, the hydration shell completely surrounds oxyluciferin; furthermore, in the molecular plane of oxyluciferin, twenty water molecules are involved with the shell. We assume that the cavity is formed owing to the hydrophobic nature that pushes water molecules away from oxyluciferin, thereby gaining surface energy through the formation of a water-vacuum interface. Considering the fact that the relative internal energy among isomers is only slightly different between the FPMD simulation and the cluster model calculation, the different hydration structures observed in them is due to the finite temperature effect or, most probably, the entropic effect. 52 Thus, the non-local hydration effect plays a significant role in determining the hydration structure, and it has a relatively minor effect on the hydration energy. 8


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H -

O

S

N

H

N

S

O

S

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H

N

S

S

N

N

S

keto

O H H

H H -

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enol H

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enolate H

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H

Figure 6: Radial distribution functions, gH−O (r), gN−H (r), and gS−H (r)

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To see the hydration structure more in detail, Fig. 6 shows a plot of the radial distribution of the oxyluciferin-water interatomic distance, gX−Y (r), where X denotes the atom that constitutes oxyluciferin (X = H, N, and S) and Y denotes either the oxygen or hydrogen atom of a water molecule (Y = O and H). The first peak of the distribution functions, gH−O (r), gN−H (r), and gS−H (r), appears at a longer distance for keto than for enol and enolate, reflecting the more hydrophobic nature of keto. For gH−O (r) and gN−H (r), the shape of the first peak is particularly sharp for enol and gentle for keto whereas the onset of the first peak is at almost the same distance for enol and keto; in contrast, for gS−H (r), the difference between the isomers is not so clear. It is worth emphasizing that the hydrophobic nature of keto is strikingly reflected in gN−H (r), where the peak position is located at a longer distance and the intensity is very small; this is due to the cavity formation. To further investigate the hydrophobic nature of keto, we counted the number of hydrogen bonds formed between oxyluciferin and nearby water molecules. For the nitrogen atom of the benzothiazole part, the number is 0.49 on average for keto, which is almost half that of enol (=0.93) and enolate (=0.98) (see also Supporting Information). The situation is similar for the hydrogen atom of the benzothiazole part; the number is significantly smaller for keto than for enol and enolate.

Oxyluciferin−water interaction energies Next, we analyze the oxyluciferin-water interaction energy defined by EiInt ≡ EiOxy+water − EiOxy − Eiwater ,

(1)

where the first to the last terms in the right-hand side are obtained from snapshots of the FPMD run by calculating the total energy of the whole system (EiOxy+water ), that of oxyluciferin isolated in vacuum by removing all water molecules (EiOxy ), and that of water molecules by taking away oxyluciferin from the cell (Eiwater ), respectively. One thousand

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snapshots were taken randomly from the FPMD to take an average. The result shows that enol is more stable than the other isomers by 0.2 eV and that keto and enolate have almost the same stability, as shown in Fig. 7. This result is consistent with the cumulative average shown in Fig. 4. Note that the value of E Oxy is smaller in magnitude than the total energy of the isomers in vacuum (Fig. 1); however, the relative value of E Oxy among the isomers is almost the same as the relative value of the total energy in vacuum. This means that the effects of the environment on oxyluciferin, including the effect of induced intramolecular vibrational excitation, are much less important than that of hydration.

keto eno eno l late

keto eno eno l late

eno eno l late

keto e eno nol late

-

=

keto

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Figure 7: Interaction energies (eV) between oxyluciferin and water molecules (E Int ) and the averaged energies of the whole system (E Oxy+water ), isolated oxyluciferin (E Oxy ), and (H2 O)64 (E water ), respectively. These values are tabulated in Supporting Information.

The interaction energy (E Int ) thus well characterizes the stability in an aqueous environment; in aqueous solution, keto loses around 0.95 eV of energy whereas enol and enolate gain 0.05 and 0.29 eV of energy, respectively. As a result, keto becomes less stable than enol and becomes as stable as enolate. 53 Therefore, we conclude that the stability order in vacuum changes from keto > enol > enolate to enol > keto ∼ enolate in aqueous solution mainly because of the difference in hydration energy caused by the different hydrophobicities.

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CONCLUSION We have performed first-principles MD simulations on keto-, enol-, and enolate-type oxyluciferin anions in aqueous solution. In a 1-ns (corresponding to 2 million MD steps) simulation, which took around 200 days using 128 Intel Xeon processors, the computational error was reduced to less than 0.1 eV, and this enabled us to discuss the stability order of oxyluciferin isomers. The simulation shows that the keto-type is less stable than the enol-type by 0.2 eV and is as stable as the enolate-type; the keto-type is by far the most stable in vacuum. The reversed stability is mainly attributed to the difference in hydration energy that reduces the relative stability of the keto-type by 0.7–0.8 eV. The different hydration energy originates from the stronger hydrophobic nature of the keto-type and is further attributable to the more neutral charge distribution realized in the benzothiazole (C7 NS) and thiazole (C3 NS) parts of the oxyluciferin molecule. The slight difference in structure among the isomers thus gives rise to large difference in hydrophobicity, causing the reversed stability in the aqueous solution. Because of the stronger hydrophobicity of the keto-type, the water molecules surrounding the oxyluciferin anion are located away from the anion, thus producing a cavity in which no water molecules exist. This indicates that the non-local effect, as typified by surface tension, plays a key role in determining the hydration structure. In contrast, the difference in hydration energy can be reproduced by a static calculation using the cluster model only when more than fifty water molecules are incorporated into the model. With a smaller number of water molecules, the keto-type is significantly more stable than the others, which contradicts the result of first-principles molecular dynamics simulation. This dependence on the number of water molecules explains why previous quantum chemistry calculations are inconsistent with the recent experimental data that suggests comparable stability among the isomers. This result also indicate that the isomeric form in a hydrated cluster is size-dependent. Although never done, a feasible route for the experimental proof may be a spectroscopic 12


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measurement of hydrated oxyluciferin anions with different cluster sizes 54–56 (note that oxyluciferin with a single water molecule has been investigated in Ref. 57 ). For oxyluciferin anions, for example, we expect that the photo absorption peak of the keto-type will be observed at 484 nm when in contact with the water cluster, (H2 O)n (where n ≤ 30), and that of the enol-type will be observed at 406 nm when in contact with more than 64 water molecules. If the oxyluciferin anion is trapped together with water molecules in a spatially limited protein in a firefly’s body, we suggest that the stability among isomers will depend on the number of water molecules. The hydration-number-dependent hydrophobicity revealed by our present theoretical data should provide an important theoretical insight into and simulate further investigation of the mechanism of firefly bioluminescence.

CALCULATION SETUP For the quantum chemistry calculations using PCM, 50,51 we placed (H2 O)n (where n = 0, 8, 11, 20, 30, 50, and 64) around oxyluciferin and PCM and started the atomic geometry optimizations within BLYP/6-311G* 58 for some initial geometries. 59 For the MD simulations, we first determined the water structure by performing first-principles Born-Oppenheimer MD for 80 water molecules in a box of 13.3723 ˚ A × 13.3723 ˚ A × 13.3723 ˚ A where the temperature is controlled using Nose-Hoover thermostats, 60–63 the time step is 0.484 fs, and the BLYP exchange-correlation functional and plane wave cut-off energy of 60 Ry for the ultrasoft pseudopotential 64 are used. We replaced oxyluciferin with 16 water molecules for the obtained equilibrium atomic geometries (see Supporting information) and performed a first-principles Born-Oppenheimer MD simulation with same calculation setup for the system including the oxyluciferin and 64 water molecules. To evaluate the interaction energies (E Int ), we used the QUANTUM ESPRESSO suite 65 and not the CPMD package 66 because of a convergence problem. We used a little large box and employed a Coulomb cutoff technique 67 only for simulating the total energies of isolated oxyluciferin (EiOxy ), because the box size used

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in the MD simulation is a little small, thereby emphasizing the interactions with oxyluciferins in different boxes (note that the use of a larger box shifts the absolute values of the total energies constantly for every case; however, it does not change the relative values of E Oxy ).

Acknowledgement We ran our MD simulations on the supercomputers installed at the Institute for Solid State Physics, University of Tokyo, and the Research Institute for Information Technology, Kyushu University. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Nos. 26400383, 15K05379, and 26610081. M. H. acknowledges the support from the Institute for Quantum Chemical Exploration. M. S. and O. S. thank Theoretical and Computational Chemistry Initiative and Computational Materials Science Initiative in the Strategic Programs for Innovative Research, MEXT, Japan.

Supporting Information Available The detailed data is given in Supporting information.

This material is available free of

charge via the Internet at http://pubs.acs.org/.

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Reverse Stability of Oxyluciferin Isomers in ... - ACS Publications

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