Molecular Dynamics Study on Dynamical Features of Reorganization

Article pubs.acs.org/JPCB

Cite This: J. Phys. Chem. B 2019, 123, 5176−5180

Molecular Dynamics Study on Dynamical Features of Reorganization Process for Nanocapsule Formed with Gear-Shaped Amphiphile Molecules Takako Mashiko,† Shuichi Hiraoka,‡ Umpei Nagashima,§ and Masanori Tachikawa*,†

Downloaded via EASTERN KENTUCKY UNIV on August 5, 2019 at 02:43:14 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Quantum Chemistry Division, Graduate School of NanoBioScience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama-city, Kanagawa 236-0027, Japan ‡ Department of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan § Foundation for Computational Science, 7-1-28 Monatojimaminami-cho, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan S Supporting Information *

ABSTRACT: We have analyzed the dynamical feature of a hexameric structure of nanocube (16) from a gear-shaped amphiphile molecule (1) upon addition of solvophobic spherical adamantane molecule (G), by means of molecular dynamics (MD) simulation, to elucidate the conversion mechanism from the hexameric nanocube G@16 to a tetrameric G@14 tetrahedron. The adamantane molecule (G) in the nanocube G@16 is located around the triple π stacking, although G in the G@14 tetrahedron is at the central position of the capsule. Our MD simulation shows that the nanocube G@16 is more fluctuated than the G@14 tetrahedron. We have also found that a demethylated nanocube G@26 is converted to a tetrameric G@23 tetrahedron due to the solvophobic effect for the adamantane molecule.

■

INTRODUCTION Induced-fit molecular recognition is profound significance in signal transduction, activation of reaction centers, and allosteric regulation. A suitable guest molecule can alter the shape, electrostatic surfaces, and the dynamical features of its host molecule to result in a stable host−guest complex.1−11 A fit between the guest(s) and the binding site of a molecular host in shape and size is a main strategy for the stabilization of host−guest complexes12 by weak molecular interactions such as hydrogen bonds,13 CH-π,14,15 π−π,16 and van der Waals (vdW) interactions.17−21 However, it has not been fully clarified the process of such conformational and or structural change at the molecule level, yet. Previously, Hiraoka et al. developed a gear-shaped amphiphile (GSA), 1, six of which self-assemble into a hexameric cubic-shaped structure, nanocube (16), in 25% aqueous methanol.22 In the case of a demethylated gear-shaped molecule (2), on the other hand, the nanocube (26) was not formed in either aqueous methanol or in pure methanol.22 Furthermore, upon addition of solvophobic spherical mole© 2019 American Chemical Society

cules such as adamantane (G) as a guest molecule, the 16 nanocube was converted into a tetrameric G@14 tetrahedron so as to tightly bind the spherical guest molecule (Figure 1).23 In this system, the nanocube can dramatically change its

Figure 1. Gear-shaped amphiphile molecules (GSAs), 1s, are selfassembled into a hexameric nanocapsule (16) in 25% aqueous methanol. Furthermore, a tetrameric tetrahedron (G@14) was induced by the encapsulation of adamantane molecule (G) in 16. Received: March 6, 2019 Revised: May 27, 2019 Published: May 28, 2019 5176

DOI: 10.1021/acs.jpcb.9b02156 J. Phys. Chem. B 2019, 123, 5176−5180

Article

The Journal of Physical Chemistry B

(CH-π and π−π interactions) between the neighboring GSAs. All the π−π distances between the centroids of two pyridyl groups are shown in Figure 2, where each GSA 1 is denoted as

structure, since the main driving force to form the nanocube is not covalent (or ionic) bonds between the GSAs but vdW force. It is quite interesting how the cubic structure of 16 is converted into the tetrahedral G@14. However, a very fast conversion prevents one from monitoring this process by most of experimental approaches. In order to elucidate the conversion mechanism from the 16 nanocube to the 14 tetrahedron by adamantane molecule (G), we analyzed the dynamical feature for G@16 and G@14 encapsulating an adamantane molecule using the molecular dynamics (MD) simulation. Recently, density functional theory calculation is applied to G@14 tetrahedron for the discussion of the stability of encapsulating adamantane molecule;24 however, no dynamical information is reported. In our MD simulation, we have found that the conversion from G@16 into G@14 occurred mainly due to the solvophobic effect.

Figure 2. All the π−π distances between the centroids of 3-pyridyl groups in the G@14 tetrahedron. Each GSA 1 is denoted as “GSAX” (X= 1−4).

■

“GSAX” (X = 1−4). The π−π distances of GSA1−GSA2, GSA1−GSA3, and GSA1−GSA4 are about 4.8 Å, which are shorter than those of GSA2−GSA3, GSA2−GSA4, and GSA3−GSA4 of 5.9 Å. This result clearly indicates that the symmetry of the 14 tetrahedron is lower than that of tetrahedron. To clarify the reason for this low symmetry, we focused on the dynamic features of the 14 tetrahedron. In order to separate the overall motions in G@14 into independent components, we carried out the principal component analysis (PCA). The PCA modes with the lowest four eigenvalues have a characteristic feature of quasidegenerated intermolecular rotational motions (Figure 3).

COMPUTATIONAL DETAILS The MD simulations of nanocapsules in aqueous methanol solvent was conducted using the AMBER package.25 For these solute molecules, we employed the GAFF26 and RESP charges27 based on HF/6-31G(d) level of calculation. Force field information is written in the ESI of our previous paper.28 Water and methanol solvent molecules are assigned the Brerendsen’s SPC/E model29 and the AMBER ff99SB force field,25 respectively. The SHAKE algorithm30 was exploited to constrain bonds involved the hydrogen atoms. The simulation temperature was set to about 300 K under the Langevin thermostat method.31 The long-range electrostatic interactions under periodic boundary conditions were evaluated using the PME method.32 The initial structures of 16 and 14 were constructed from their crystal structures.22,23 First, a geometry optimization by energy minimization was carried out for the 16 and 14 in the gas phase. Meanwhile, the initial coordinates for 26 and 24 were generated from the optimized 16 and 14 structures by replacing the methyl groups in 1 with hydrogen atoms, and a subsequent geometry optimizations were performed. Then, 1711 water and 2289 methanol molecules were set around each nanocapsule in order to include the explicit solvent effect of 25% aqueous methanol, and an additional geometry optimization for only solvent molecules was carried out. Isobaric− isothermal ensemble (NPT) simulations were performed to optimize the simulation box sizes. After the NPT equilibration, the density of the solution in aqueous methanol solvent was set to the experimental value of 0.87 g/cm3. In order to discuss the effect of the adamantane molecule (G), we calculated the nanocubes containing adamantine molecule, such as G@14, G@16, G@24, and G@26. Then, 10 production runs of both systems were executed in the canonical ensemble (NVT) for 1.8 ns (900 000 steps) after a thermal equilibration of 0.2 ns (100 000 steps) from different initial structures. Finally, in order to see the conversion process, we carried out one production run in the NVT for 20.0 ns (10 000 000 steps).

■

Figure 3. Lowest PCA modes with intermolecular rotational motions. (a and b) Different views at the same PCA mode. The front GSA in part a rotates in a counterclockwise direction, while the rest of tree GSAs behind the front GSA in a clockwise direction. Part b indicates the opposite view, showing the three GSAs rotating in the same direction.

One molecule of 1 in G@14 rotates in a counterclockwise direction (Figure 3a), while the other three GSAs 1s rotate in a clockwise direction. We found that the dynamic motion of the G@14 tetrahedron consists of two parts derived from 13 and 1, which should be a main reason for the low symmetry of G@14. Next, we focus on the position of the adamantane molecule (G) in the G@14 and G@16 capsules. Figure 4 shows the distributions of the distances between the centroid of the nanocapsule (14 or 16) and that of the adamantane molecule encapsulated in the nanocapsules, in which the peak positions for 14 and 16 are found at 0.5 and 2.6 Å, respectively. This result clearly indicates that the adamantane molecule in the 14 tetrahedron is located at around the center of the capsule. On the other hands, the adamantane molecule in the G@16

RESULTS AND DISCUSSION

Structures of 14 and 16 Encapsulating Adamantane (G). The adamantane molecule (G) in the 14 tetrahedron is fully surrounded by the four GSAs of the 14 tetrahedron, where GSAs are connected to each other through vdW interactions 5177

DOI: 10.1021/acs.jpcb.9b02156 J. Phys. Chem. B 2019, 123, 5176−5180

Article

The Journal of Physical Chemistry B

Figure 4. Distribution of the distances between the centroid of the G@14 or G@16 nanocapsule and that of adamantane molecule.

Figure 5. Time evolution of the distances between the centroid of the adamantane molecule encapsulated in 26 and the centroid of each GSAX (X = 1−6) during 0.0−2.0 ns. Purple, green, light blue, orange, yellow, and blue plots indicate the distances for GSA1−GSA6, respectively.

nanocube is located at the position far from the center of the capsule. Thus, it is obvious that the adamantane molecule in the G@16 nanocube is faced with a part of interior surface of 16. A broader peak for G@16 in Figure 4 also indicates that the position of the adamantane molecule in G@16 is more fluctuated than that in G@14. Two-dimensional (2D) distribution analysis of the adamantane in 16 (Figures S1 and S2) indicates that the adamantane is located close to one of the apexes of the cube. These results indicate that the adamantane molecule is not located at around the centroid of the nanocube but cross to the inner surface of the nanocube. In experiment, the addition of adamantane (G) in a solution of 1 6 caused the conversion of G@1 6 into the G@1 4 tetrahedron.22,23 In our simulation, however, the G@16 nanocube was not converted into the G@14 during our MD simulation time until 1.8 ns because metastable G@16 has longer lifetime than the simulation time scale. Thus, to follow the conversion process from the nanocube to the tetrahedron, we carried out the MD simulation of the nanocube G@26 consisting of GSAs 2, in which three methyl groups of 1 are replaced with hydrogen atoms. Due to lower stability of the 26 nanocube than 16, which is caused by decreasing in the vdW interactions around the three methyl groups, the lifetime of the 26 nanocube would be shorter than the simulation time scale. Conversion Process from G@2 6 into G@23. As expected, the G@26 nanocube was collapsed in all the trajectories. To analyze the conversion process in detail, we focus on the distance between the centroid of the adamantane molecule and the centroid of each GSAX (X = 1−6) (Figure 5). At the early stage (until 0.5 ns), the structure of 26 does not drastically change from the initial structure. In particular, the blue and green lines are almost perfectly overlapped at around 6 Å. From 0.5 ns, the nanocube 26 stretches along the C3 axis of the nanocube, resulting in the separation of the two fragments; fragments 1 (GSAs 1, 3, and 5) and 2 (GSAs 2, 4, and 6). Figure 6 shows the distances between the centroid of the adamantane molecule and the centroid of each GSAX (X = 1− 6) during 2.0−20.0 ns. During 5.0−6.0 ns all the distances gradually changed, where the structure of the nanocube is stretched as shown in Figure 7. Triple π staking of the nanocube 26 is divided into a double π stack and a 3-pyridyl group as shown in right side of Figure 7. In our previous study, we found that the nanocube has two main important interactions: the π − π stacking interactions between two 3-

Figure 6. Time evolution of the distances between the centroid of the adamantane molecule encapsulated in 26 and the centroid of each GSAX (X = 1−6) during 2.0−20.0 ns. Purple, green, light blue, orange, yellow, and blue plots indicate the distances for GSA1−GSA6, respectively.

Figure 7. Representative snapshot of the structure of the G@26 nanocube during 5.0−6.0 ns. White, cyan, and blue indicate hydrogen, carbon, and nitrogen atoms in 26, respectively. Red indicates the adamantane molecule encapsulated in 26.

pyridyl groups and the CH−π interactions.28 As GSA 2 lacks three p-tolyl methyl groups, stability of the 26 nanocube mainly depends on π−π interactions. Although the structure of the G@26 nanocube shown in Figure 7 is deformed from a cube, this distorted structure is weakly stabilized by the double π stacking interaction. 5178

DOI: 10.1021/acs.jpcb.9b02156 J. Phys. Chem. B 2019, 123, 5176−5180

Article

The Journal of Physical Chemistry B In order to contact between each GSA and adamantane guest molecules, 26 collapsed at point of triple π stackings. After about 7.0 ns, the distance for GSA4 is about 5 Å, which is similar to the distances for GSA2 and GSA6. This clearly indicates that three molecules of 2 (GSA2, GSA4, and GSA6) directly contact the adamantane molecule to form a G@23 open-nanocapsule (Figure 8). The open-nanocapsule is enthalpically stabilized by the π stacking between the GSAs in 23 and by the vdW interactions between 23 and the guest molecule (G).

■

Two-dimensional distribution of the distances between the centroid of the 16 nanocube and that of each molecule 1 and two-dimensional distribution of the distances between the centroid of adamantane molecule and that of each molecule 1 (PDF)

AUTHOR INFORMATION

Corresponding Author

*(M.T.) E-mail: [email protected]. ORCID

Shuichi Hiraoka: 0000-0002-9262-4747 Masanori Tachikawa: 0000-0002-5489-5714 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by JSPS Grants-in-Aid for Scientific Research on Innovative Areas “Dynamical Ordering of Biomolecular Systems for Creation of Integrated Functions” (JP25102005, JP25102001, and 16H00780). This work was also partly supported at the Research center for Computational Science (RCCS), Okazaki, Japan.

Figure 8. Representative snapshot of the G@23 open-nanocapsule. Color label is the same as is shown in the caption of Figure 7.

■

As shown in Figures 7 and 8, the G@26 nanocube was converted into the G@23 open-nanocapsule, where four double π stackings stabilize the structure. The inner space of the 26 nanocube is larger than the size of the adamantane, so the interaction between the inner surface of the 26 nanocube and the adamantine is weak. Therefore, the GSAs in 26 are rearranged so as to fit the adamantane by the “induced-fit” transition of 26 into the G@23 open-faced tetrahedron. This result suggests that the conversion of G@16 to G@14 induced by the encapsulation of adamantine molecule (G) also takes place in a similar way.

ABBREVIATIONS MD, molecular dynamics; AMBER, assisted model building with energy refinement; GAFF, general AMBER force field; RESP, restrained electrostatic potential; PME, particle mesh Ewald

■

(1) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Molecular Encapsulation. Angew. Chem., Int. Ed. 2002, 41, 1488−1508. (2) Koshland, D. E. The Key−Lock Theory and the Induced Fit Theory. Angew. Chem., Int. Ed. Engl. 1995, 33, 2375−2378. (3) Körner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek, J., Jr. A Self-Assembled Cylindrical Capsule: New Supramolecular Phenomena through Encapsulation. Chem. - Eur. J. 2000, 6, 187−195. (4) Yoshizawa, M.; Kusukawa, T.; Fujita, M.; Sakamoto, S.; Yamaguchi, K. Cavity-Directed Synthesis of Labile Silanol Oligomers within Self-Assembled Coordination cages. J. Am. Chem. Soc. 2001, 123, 10454−10459. (5) Ziegler, M.; Brumaghim, J. L.; Raymond, K. N. Stabilization of a Reactive Cationic Species by Supramolecular Encapsulation. Angew. Chem., Int. Ed. 2000, 39, 4119−4121. (6) Kang, J.; Rebek, J., Jr. Acceleration of a Diels−Alder Reaction by a Self-Assembled Molecular Capsule. Nature 1997, 385, 50−52. (7) Fiedler, D.; Bergman, R. G.; Raymond, K. N. Supramolecular Catalysis of a Unimolecular Transformation: Aza-Cope Rearrangement within a Self-Assembled Host. Angew. Chem., Int. Ed. 2004, 43, 6748−6751. (8) Yoshizawa, M.; Tamura, M.; Fujita, M. Diels-Alder in Aqueous Molecular Hosts: Unusual Regioselectivity and Efficient Catalysis. Science 2006, 312, 251−254. (9) Shivanyuk, A.; Rebek, J., Jr. Social Isomers in Encapsulation Complexes. J. Am. Chem. Soc. 2002, 124, 12074−12075. (10) Shivanyuk, A.; Rebek, J., Jr. Isomeric Constellations of Encapsulation Complexes Store Information on the Nanometer Scale. Angew. Chem., Int. Ed. 2003, 42, 684−686. (11) Yamanaka, M.; Rebek, J., Jr. Constellational Diastereomers in Encapsulation Complexes. Chem. Commun. 2004, 15, 1690−1691. (12) Mecozzi, S.; Rebek, J., Jr. The 55% Solution: A Formula for Molecular Recognition in the Liquid State. Chem. - Eur. J. 1998, 4, 1016−1022.

■

CONCLUSION In order to elucidate the induced-fit conversion mechanism from the hexameric nanocube to the tetrameric capsule by the encapsulation of an adamantane molecule (G), first, we analyzed the dynamic feature of G@16 and G@14 encapsulating an adamantane molecule using the molecular dynamics (MD) simulations. The modes of low eigenvalues by principal component analysis of 14 show characteristic feature of intermolecular rotational motions; One molecule of 1 in G@ 14 rotates in a counterclockwise direction, while the other three molecules of 1s in clockwise direction. We have found that the dynamic motion of the G@14 tetrahedron is caused by two parts, 13 and 1. To follow the conversion process from G@16 to G@14 in a realistic computational time scale, we carried out the MD simulation of the demethylated nanocube G@26 with an adamantane molecule. Our long time MD simulations indicate that the conversion of G@26 into G@23 takes place so as to enhance the solvophobic effect and vdW interactions for the adamantane molecule by induced-fit and that breaking the triple π stacking interaction in the nanocube is the first structural change of the nanocube toward this transformation.

■

REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.9b02156. 5179

DOI: 10.1021/acs.jpcb.9b02156 J. Phys. Chem. B 2019, 123, 5176−5180

Article

The Journal of Physical Chemistry B (13) Yamanaka, M.; Ishii, K.; Yamada, Y.; Kobayashi, K. Tunable Capsule Space: Self-Assembly of Hemispherical Cavitands with Hydrogen-Bonding Linkers. J. Org. Chem. 2006, 71, 8800−8806. (14) Manimaran, B.; Lai, L.-J.; Thanasekaran, P.; Wu, J.-Y.; Liao, R.T.; Tseng, T.-W.; Liu, Y.-H.; Lee, G.-H.; Peng, S.-M.; Lu, K.-L. CH···π Interaction for Rhenium-Based Rectangles: An Interaction That Is Rarely Designed into a Host−Guest Pair. Inorg. Chem. 2006, 45, 8070−8077. (15) Pluth, M. D.; Raymond, K. N. Reversible Guest Exchange Mechanisms in Supramolecular Host−Guest Assemblies. Chem. Soc. Rev. 2007, 36, 161−171. (16) Pérez, E. M.; Martín, N. π−π Interactions in Carbon Nanostructures. Chem. Soc. Rev. 2015, 44, 6425−6433. (17) McIntosh, G. C.; Tománek, D.; Park, Y. W. Energetics and Electronic Structure of a Polyacetylene Chain Contained in a Carbon Nanotube. Phys. Rev. B: Condens. Matter Mater. Phys. 2003, 67, 125419. (18) Orellana, W.; Vásquez, S. O. Endohedral Terthiophene in Zigzag Carbon Nanotubes: Density Functional Calculations. Phys. Rev. B: Condens. Matter Mater. Phys. 2006, 74, 125419. (19) Horn, P.; Kertesz, M. Conformational Preferences of βCarotene in the Confined Spaces inside Carbon Nanotubes. J. Phys. Chem. C 2010, 114, 12139−12144. (20) Milko, M.; Ambrosch-Draxl, C. Energetics and Structure of Organic Molecules Embedded in Single-Wall Carbon Nanotubes from First Principles: The Example of Benzene. Phys. Rev. B: Condens. Matter Mater. Phys. 2011, 84, 085437. (21) Kuwahara, R.; Kudo, Y.; Morisato, T.; Ohno, K. Encapsulation of Carbon Chain Molecules in Single-Walled Carbon Nanotubes. J. Phys. Chem. A 2011, 115, 5147−5156. (22) Hiraoka, S.; Harano, K.; Shiro, M.; Shionoya, M. A SelfAssembled Organic Capsule Formed from the Union of Six Hexagram-shaped Amphiphile Molecules. J. Am. Chem. Soc. 2008, 130, 14368−14369. (23) Hiraoka, S.; Harano, K.; Nakamura, T.; Shiro, M.; Shionoya, M. Induced-Fit Formation of a Tetrameric Organic Capsule Consisting of Hexagram-Shaped Amphiphile. Angew. Chem., Int. Ed. 2009, 48, 7006−7009. (24) Pichierri, F. Adamantane Template Effect on the Self-Assembly of a Molecular Tetrahedron: A Theoretical Analysis. Chem. Phys. Lett. 2018, 713, 149−452. (25) Case, D. A.; Cerutti, D. S.; Cheatham, T. E., III; Darden, T. A.; Duke, R. E.; Giese, T. J.; Gohlke, H.; Goetz, A. W.; Greene, N.; Homeyer, N.; et al. AMBER 16; University of California: San Francisco, CA, 2016. (26) Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and Testing of a General Amber Force Field. J. Comput. Chem. 2004, 25, 1157−1174. (27) Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A WellBehaved Electrostatic Potential Based Method Using Charge Restraints for Deriving Atomic Charges: the RESP Model. J. Phys. Chem. 1993, 97, 10269−10280. (28) Mashiko, T.; Hiraoka, S.; Nagashima, U.; Tachikawa, M. Theoretical Study on Substituent and Solvent Effects for Nanocubes Formed with Gear-Shaped Amphiphile Molecules. Phys. Chem. Chem. Phys. 2017, 19, 1627−1631. (29) Berendsen, H. J. C.; Grigera, J. R.; Straatsma, T. P. The Missing Term in Effective Pair Potentials. J. Phys. Chem. 1987, 91, 6269− 6278. (30) Miyamoto, S.; Kollman, P. A. Settle: An Analytical Version of the SHAKE and RATTLE Algorithm for Rigid Water Models. J. Comput. Chem. 1992, 13, 952−962. (31) Feller, S. E.; Zhang, Y.; Pastor, R. W.; Brooks, B. R. Constant Pressure Molecular Dynamics Simulation: The Langevin Piston method. J. Chem. Phys. 1995, 103, 4613−4621. (32) Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An Nlog(N) Method for Ewald Sums in Large Systems. J. Chem. Phys. 1993, 98, 10089−10092.

5180

DOI: 10.1021/acs.jpcb.9b02156 J. Phys. Chem. B 2019, 123, 5176−5180