Threading or Tumbling? Insight into the Self-Inclusion Mechanism of

Article pubs.acs.org/JPCC

Threading or Tumbling? Insight into the Self-Inclusion Mechanism of an altro-α-Cyclodextrin Derivative Ying Liu,† Christophe Chipot,‡,§ Xueguang Shao,† and Wensheng Cai*,† †

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), State Key Laboratory of Medicinal Chemical Biology (Nankai University), Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China ‡ Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana−Champaign, Unité Mixte de Recherche No. 7565, Université de Lorraine, B.P. 70239, 54506 Vandœuvre-lès-Nancy cedex, France § Theoretical and Computational Biophysics Group, Beckman Institute, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States S Supporting Information *

ABSTRACT: An altro-α-cyclodextrin (altro-α-CD) derivative bearing an adamantyl end group can form a pseudo[1]rotaxane through the self-inclusion of its arm into the CD cavity. Yet, how the bulky end group translocates from the secondary side of the altro-α-CD to its primary side to form the pseudo[1]rotaxane remains somewhat unclear. In the present work, the atomic-level mechanism that underlies the formation of the self-inclusion complex was investigated by means of molecular dynamics simulations combined with microsecond time scale free-energy calculations. Two possible transition pathways leading to the formation of the same self-inclusion structure were considered, namely, threading of the adamantyl group through the altro-α-CD cavity, and tumbling of the altropyranose unit of altro-α-CD. The free-energy profiles characterizing the threading and the tumbling pathways were determined, revealing in each case the free-energy barrier. For the former pathway, the freeenergy barrier with respect to the unbound state amounts to 53.6 kcal/mol, unphysically high to make the threading route feasible. Conversely, for the latter pathway, a 16.0 kcal/mol free-energy barrier is measured, indicating that the formation of the pseudo[1]rotaxane may result from the tumbling of the altropyranose unit bearing the adamantyl arm.

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INTRODUCTION Cyclodextrins (CDs) are cyclic oligomers of 1,4-linked, α-Dglucopyranose monomers. The nanosize cavities of CDs are notorious to possess outstanding ability to recruit guest molecules through primarily nonelectrostatic interactions, leading to the formation of inclusion complexes.1−4 Owing to this remarkable property, CDs are superior candidates to construct rotaxanes, polyrotaxanes, catenanes, and other similar molecular nanomachines.5−7 The macrocycles of CDs exhibit remarkable structural rigidity due to the interglucopyranose hydrogen bond network formed between the 2-OH and 3-OH groups, which stems from the adoption of the energetically favorable 4 C 1 chair conformation of each glucopyranose unit. Size matching of the cavity of CD and the guest molecule is thought to be one of the most crucial determinants of the binding affinity. For example, compared to α- and γ-CD, β-CD yields the strongest interaction with adamantane.8−13 Adamantane is too large a molecule to penetrate completely into the α-CD cavity. Nevertheless, it is too small to be tightly embedded in the cavity of a γ-CD. An interesting phenomenon was, however, observed by Harada and co-workers,14 namely, an altro-α-CD connected to an adamantyl group via cinnamamide, as shown in © 2014 American Chemical Society

Figure 1A, can form a pseudo[1]rotaxane through self-inclusion. H NMR spectra reveal that the cinnamamide moiety is included in the cavity of altro-α-CD as the guest molecule, while the adamantyl group lies outside of the narrower rim. In light of this observation, the following question ought to be addressed: how can the large adamantyl moiety pass through the narrow side of the altro-α-CD to form the self-inclusion complex? In the altro-α-CD derivative of Figure 1, the sugar unit bearing the arm moiety is an α-D-altropyranose unit, weakening hydrogen-bonding interactions with its neighboring glucopyranose units at the secondary hydroxyl side, as shown in Figure S1 of the Supporting Information. The weaker hydrogen-bond network may render the altro-α-CD macrocycle more flexible than the native α-CD (see Figure S2 of the Supporting Information). On the basis of this analysis and subsequent experiments, Harada et al.14 put forth a threading mechanism, whereby the flexibility of the cavity may allow threading of the bulky end group and formation of the inclusion complex, as illustrated in Figure 1B. 1

Received: April 20, 2014 Revised: July 23, 2014 Published: July 28, 2014 19380

dx.doi.org/10.1021/jp503866q | J. Phys. Chem. C 2014, 118, 19380−19386

The Journal of Physical Chemistry C

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Figure 1. (A) Chemical structure of the altro-α-CD derivative. Schematic illustration of the threading (B) and tumbling (C) pathways leading to the pseudo[1]rotaxane.

In later experiments, Harada et al.15 connected two altro-αCD molecules together by a long chain. Surprisingly, a similar self-inclusion complex still formed and a pseudo[1]rotaxane dimer was observed. It would appear that one altro-α-CD threading through the cavity of another altro-α-CD is physically impossible. A tumbling mechanism was, therefore, proposed in their study, whereby the altropyranose unit of an altro-α-CD could rotate about the axis of an α(1,4) bond (see Figure 1C) as a result of the weak conformational restriction by hydrogen bonds, hence, leading to the formation of the pseudo[1]rotaxane dimer. The main thrust of the present work is to investigate the mechanism that underlies the formation of the pseudo[1]rotaxane of Figure 1 by examining at the atomic level two putative transition pathways (see Figure 1B,C). Toward this end, classical, all-atom molecular dynamics (MD) simulations combined with microsecond time scale free-energy calculations have been performed. The free-energy profiles delineating the threading and the tumbling processes were determined, from whence the most likely pathway toward the formation of the pseudo[1]rotaxane was inferred.

Figure 2. Two simplified models utilized to explore the putative transition pathways. (A) Threading an adamantane through the altroα-CD cavity. (B) Tumbling an altropyranose unit about the axis of an α(1,4) bond. To describe a continuous tumbling process, the transition pathway spans −300° ≤ θ ≤ +100°.

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COMPUTATIONAL METHODS Molecular Models. To investigate at the atomic level the threading and the tumbling pathways, two simplified molecular models were constructed. For the threading pathway, the adamantane molecule was placed from the onset at the secondary side of the altro-α-CD, 10 Å away from its center of mass, as shown in Figure 2A. Since the primary objective of this simulation is to assess the steric hindrances between the bulky adamantyl moiety and the cavity of the CD, the cinnamamide molecule connecting the adamantyl group and the altro-α-CD

was not taken into account to simplify the molecular assembly. The initial coordinates of the mono-altro-α-CD were obtained from the available crystal structure of α-CD16 and were modified accordingly. In aqueous solution, mono-altro-α-CD navigates between two equilibrium states (1C4 and 4C1) due to the altropyranose unit, and the 1 C 4 conformation is 19381



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For the tumbling pathway, the transition coordinate, θ, as depicted in Figure 2B, was chosen as the dihedral angle between the altropyranose unit and the plane formed by the six glycosidic oxygen atoms of the altro-α-CD. In order to describe a complete and continuous tumbling process, the explored transition pathway spanned −300° ≤ θ ≤ +100°, wherein the interval between −300° and −180° corresponds to that between +60° and +180°. The backbone of the altro-α-CD was softly restrained, except for the altropyranose unit, which was left to rotate freely. To increase the efficiency of the calculations, the transition pathway was broken down into five consecutive windows. Instantaneous values of the force were stored in 1° wide bins. The total simulation time amounted to 1.52 μs.

thermodynamically more stable than the 4C1 conformation.14 The 1C4 chair conformation was, therefore, chosen for the initial configuration for the altropyranose unit. For the tumbling pathway, on the basis of similar considerations, the mono-altro-α-CD rather than the altro-α-CD derivative was employed to investigate the tumbling of the altropyranose unit (see Figure 2B). The two molecular assemblies were immersed independently in a box of water. The initial dimensions were 33.5 × 33.3 × 35.5 Å3, featuring 1127 water molecules, and 33.6 × 31.9 × 30.6 Å3, featuring 940 water molecules. A 10 ns equilibrium MD simulation was performed for each molecular assembly prior to free-energy calculations. The altropyranose unit was observed to remain in its 1C4 chair conformation in the course of the 10 ns MD simulation. An additional 10 ns MD simulation was carried out for the native α-CD as a basis of comparison. Analyses of the MD trajectories for the altro- and the native α-CD show that the macrocycle of the former is more flexible than that of the latter and is significantly distorted toward an elliptical shape (see Figure S3 of the Supporting Information). Two molecular models corresponding to the noninclusion and self-inclusion states of the altro-α-CD derivative were constructed. The geometry of these molecules was optimized using a conjugate-gradient algorithm. The two molecular assemblies were subsequently immersed in a water bath. The initial size of the water box was 34.0 × 38.9 × 40.4 Å3 for each solvated assembly, involving 1550 water molecules. Molecular Dynamics Simulations. All the MD simulations reported here were performed using the parallel, scalable MD program NAMD17 with the CHARMM 36 force field18−20 and the TIP3P water model.21 Langevin dynamics was applied to control the temperature at 303.15 K, and the pressure was maintained at 1 atm employing the Langevin piston method.22 Covalent bonds involving hydrogen atoms were constrained to their equilibrium length by means of the SHAKE/RATTLE algorithm,23,24 except for water molecules, for which the SETTLE algorithm was applied.23 Long-range electrostatic forces were evaluated using the particle mesh Ewald scheme,25 and a smoothed 12 Å spherical cutoff was used to truncate van der Waals interactions. The r-RESPA multiple time-step algorithm was applied to integrate the equations of motion with a time step of 2 and 4 fs for short- and long-range interactions. Visualization and analysis of MD trajectories were carried out with the VMD package.26 Free-Energy Calculations. The free-energy profiles delineating the threading of adamantane and the tumbling of the altropyranose unit were generated using the adaptive biasing force (ABF)27−31 method implemented within the collective variables module32 of NAMD. For the threading pathway, the transition coordinate, ξ, was defined as the projection onto the z-axis of the distance between the center of mass of adamantane and that of the CD glycosidic oxygen atoms (see Figure 2A). To ensure proper threading, the glycosidic oxygen atoms were restrained by means of a weak harmonic potential with a force constant of 1.0 kcal/mol/Å2. The transition pathway, extending from −10 to +10 Å, was broken down into three nonoverlapping windows. Instantaneous values of the force were accrued in bins 0.1 Å wide. The variation of the free energy, ΔG(ξ), was determined by integrating the average force acting on ξ. The simulation time was extended incrementally to probe the convergence of the free energy, leading to a 0.52 μs simulation.

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RESULTS AND DISCUSSION Free-Energy Profile for Threading an Adamantane through the altro-α-CD Cavity. The free-energy profile along ξ, characterizing adamantane threading through the altroα-CD cavity (see Figure 2A), is depicted in Figure 3A. As can be observed, two relatively flat regions, namely, −10 ≤ ξ ≤ −7 and +5 ≤ ξ ≤ +10 Å, are separated by a sharply peaked, high free-energy barrier spanning −4 ≤ ξ ≤ +5 Å. These two flat regions prefacing and following the free-energy barrier correspond to the unbound states of adamantane. The free energy gently subsides from −7 to −4 Å as adamantane approaches altro-α-CD, leading to the global minimum at around −3.8 Å, wherein the adamantane molecule is partially included in the altro-α-CD cavity (see Figure 3B). As adamantane moves deeper into the altro-α-CD cavity, a significantly high free-energy barrier emerges owing to steric hindrances. The structure of the complex corresponding to the maximum at +0.8 Å, wherein the bulky adamantane molecule is completely encapsulated in the altro-α-CD cavity, is shown in Figure 3C. The conspicuously large free-energy barrier with respect to the stable state, 53.6 kcal/mol, indicates that adamantane cannot reach the narrow side of altro-α-CD. To demonstrate that the transition coordinate, ξ, used herein constitutes an appropriate choice, a committor analysis was undertaken.33,34 Distributions of the committor, pA, at three positions near the free-energy maximum were determined (see Figure 3A). The distribution corresponding to the maximum of the PMF is Gaussian-like and peaked at the probability of 0.5 (see Figure S4 of the Supporting Information), suggesting that the collective variable utilized represents a reasonable model of the reaction coordinate for the threading process. The geometric change of the altro-α-CD cavity during threading was monitored by measuring the average area of the central disk spanned by the six glycosidic oxygen atoms of the altro-α-CD. As illustrated in Figure 3D, a marked expansion of the cavity can be observed where the free-energy barrier arises. Moreover, the conformational change of the altro-α-CD was monitored during threading. In the structure corresponding to the free-energy barrier of Figure 3A, each glucopyranose unit of the altro-α-CD tends to isomerize from 4C1 chair conformation to the energy unfavorable twist-boat conformation, owing to the deformation of CD cavity. The altropyranose unit was, however, found to maintain its 1C4 chair conformation in the course of the whole threading process, without noticeable conformational change from 1C4 to 4C1, at apparent variance with experiment.14 Therefore, although altro-α-CD is considered to be somewhat more flexible than α-CD, the size mismatch between the 19382



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increase of the free energy. The structure in Figure 5B shows that, as the hydroxyl group reached the center of the cavity, the altropyranose unit tilted roughly parallel to the midplane. As the tumbling proceeded, the hydroxyl group moved out of the cavity, hence leading to a decrease of the free energy to a local minimum, corresponding to point C of the PMF. It can be observed in Figure 5C that the primary hydroxyl group turned over and a hydrogen bond formed between O5 and O3, thus stabilizing the structure to some extent. As the altropyranose unit turned further, this hydrogen bond got disrupted, and then both of its secondary hydroxyl groups entered the cavity of altro-α-CD (see Figure 5D), thereby causing a significant increase of the free energy. Solvation of these two hydrophilic hydroxyl groups resulted in a sequential decrease of the free energy, leading to the local minimum at point E. The corresponding structure shows a circle-shaped cavity (see Figure 5E). To demonstrate that the path delineating the tumbling of altropyranose unit is a kinetically relevant one, we determined the committor distribution at the maximum of the free-energy profile, i.e., point D of the PMF (see Figure 4A). It can be found that this distribution is Gaussian-like and peaked at the probability of 0.5 (see Figure S5 of the Supporting Information), indicating that the collective variable, θ, constitutes a suitable transition coordinate for exploring the tumbling of a monomer in a cyclic oligomer. Conformational changes of the altropyranose unit can be observed in the course of the tumbling process. Initially, the altropyranose unit remains in a 1C4 chair conformation within the interval spanning ca. −30° ≤ θ ≤ +100°. As tumbling proceeds, it isomerizes into a twist-boat form in the range of θ values from −230° to −30°. Eventually, it tends to adopt a 4C1 chair conformation in the range of θ values from −300° to −230°. As can be seen in Figure 4A, two free-energy barriers need to be overcome sequentially to tumble from the global minimum at point A to the local minimum at point E. The total free-energy difference of 16.0 kcal/mol between points A and D is much lower than the barrier height of 53.6 kcal/mol in the threading pathway. It follows that the self-inclusion structure of the altro-α-CD derivative is likely to result from tumbling of the altropyranose unit bearing the arm moiety, rather than threading of the adamantyl group. Hydrogen Bonds and Solvent-Accessible Surface Area. To delve further into the above observations, the evolution of the hydrogen bonds between the altropyranose unit and its two neighboring glucopyranose units was monitored in the course of the whole tumbling process, as shown in Figure 4B. The two deepest valleys of the curve appear in the region of −250° ≤ θ ≤ −200° and −50° ≤ θ ≤ +50°, corresponding to the two barriers of the PMF delineating tumbling. In these two valleys, the altropyranose unit is approximately parallel to the midplane of the altro-α-CD, resulting in the absence of hydrogen bonds. The peak emerging between −120° and −70° is mirrored by the local minimum of the PMF in the same region, which can be rationalized by the hydrogen bond formed between O5 and O3, as shown in Figure 5C. This result indicates that hydrogen bonding between the altropyranose unit and its two neighboring glucopyranose units partly reflects the fluctuation of the free energy during the tumbling process. Moreover, the solvent-accessible surface areas (SASAs) of the primary hydroxyl group and the two secondary hydroxyl groups of the altropyranose monomer were measured

Figure 3. (A) Free-energy profile characterizing the threading process along ξ. Snapshots of the inclusion complex of adamantane with altroα-CD (B) at the global minimum of the PMF, ca. ξ = −3.8 Å, and (C) at the barrier of the PMF, ca. ξ = +0.8 Å. For clarity, water molecules are omitted. (D) Fluctuation in the course of the threading process of the area of the central plane formed by the six glycosidic oxygen atoms of the altro-α-CD.

cavity and the guest makes it impossible for adamantane to thread through altro-α-CD. In other words, it would appear reasonable to rule out the threading route to rationalize the selfinclusion phenomena observed with altro-α-CD derivative. Free-Energy Profile for Tumbling an Altropyranose Unit. In the initial structure of altro-α-CD for the ABF simulation, the tilt angle of the altropyranose unit with respect to the mean plane of the CD, θ, is measured to be 75°. The PMF characterizing the tumbling of the altropyranose unit (see Figure 2B) is depicted in Figure 4A. The horizontal arrow denotes the tumbling direction of the altropyranose monomer. The structures corresponding to the inflection points, from A to E in the PMF, are shown in Figure 5A−E. The structure in Figure 5A, i.e., the global minimum of the PMF (at point A), is very similar to the initial configuration of altro-α-CD. As the altropyranose unit tumbled toward the midplane of the altro-αCD, the hydrophilic hydroxyl group at the primary side gradually entered the hydrophobic cavity, resulting in an 19383



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Figure 4. (A) Free-energy profile characterizing the tumbling of the altropyranose monomer of altro-α-CD along θ. The values of the dihedral angle corresponding to inflection points A to E of the PMF are 75°, −14°, −80°, −192°, and −276°, respectively. (B) Evolution of the average number of hydrogen bonds formed between the altropyranose unit and two neighboring glucopyranose units during tumbling. The hydrogen-bonding criteria are (i) the angle O−H···O > 135° and (ii) the distance O···O < 3.5 Å. Evolution of the solvent-accessible surface area (SASA) of (C) the primary hydroxyl group and (D) the secondary hydroxyl groups of the altropyranose unit in the course of tumbling.

chain-like cinnamamide moiety is located outside the cavity. The cinnamamide moiety is found to form an intramolecular hydrogen bond with one secondary hydroxyl group of the CD, hence, stabilizing the noninclusion structure. The top view shows an elliptic cavity owing to the 1C4 conformation of the altropyranose unit, similar to the structure in Figure 5A. For the self-inclusion structure, the 4C1 chair conformation of the altropyranose unit leads to a perfectly circular cavity, as shown in the top view in Figure 6B. The hydrophobic alkenyl and phenyl groups of the cinnamamide moiety are included in the hydrophobic cavity, compensating for the increment of free energy caused by the unfavorable 4C1 conformation of the altropyranose unit. The experimental result by the Harada group14 shows that the two states of the altro-α-CD derivative possess similar stability and that the activation free energy for the interconversion between these two states is about 20.9 kcal/mol. This experimental activation free energy is close to the calculated one for the tumbling pathway (16.0 kcal/mol), albeit significantly lower than that of the threading pathway (53.6 kcal/mol). This observation suggests once again that interconversion between noninclusion and self-inclusion of the altro-α-CD derivative occurs based on the tumbling mechanism rather than the threading one. The difference of 4.9 kcal/mol between the experimental and the calculated activation free energy may be ascribed to an absence of the cinnamamide moiety and the adamantyl group in the simulation of the tumbling process.

separately, as shown in Figure 4C,D. The pronounced valley in the region of −100° ≤ θ ≤ +50° (Figure 4C) corresponds to the primary hydroxyl group entering into the hydrophobic cavity of altro-α-CD, which is mirrored in the free-energy barrier spanning −80° ≤ θ ≤ +30° (Figure 4A). The significant valley in the region of −250° ≤ θ ≤ −100° (Figure 4D) indicates that the two secondary hydroxyl groups tumbled into the hydrophobic cavity, resulting in an unfavorable free-energy change. Put together, it can be concluded that the free-energy barriers in the PMF that characterizes the tumbling pathway arise from the conjunction of breaking hydrogen bonds between the altropyranose unit and its neighbors, and the desolvation of the hydroxyl groups of the altropyranose unit. It is worth noting that simplified molecular models were employed to investigate the above-mentioned self-inclusion pathways of the altro-α-CD derivative. In the case of the threading pathway, the molecular model contains an adamantane molecule and an altro-α-CD, without consideration of the arm (see Figure 2A). Conversely, for the tumbling pathway, only a mono-altro-α-CD was involved (see Figure 2B). It follows that the end products for these two models are totally distinct, and as a result, the free-energy difference between the end products for the two pathways cannot be compared in a straightforward fashion (see Figures 3A and 4A). Structural Analysis of the altro-α-CD Derivative. In addition to the ABF simulation of mono-altro-α-CD, we also constructed two models for an altro-α-CD derivative, corresponding to the noninclusion state and self-inclusion one, wherein the altropyranose unit adopts 1C4 and 4C1 chair conformation, respectively. Thirty nanoseconds of equilibrium MD simulations were carried out for 30 ns in water for both molecular assemblies. As presented in Figure 6A, the altro-αCD derivative tends to form a bowl-like structure when the

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CONCLUSIONS

In this contribution, we have investigated at the atomic level two possible self-inclusion pathways of an altro-α-CD derivative with a bulky adamantyl group, namely, through threading and tumbling. For the threading pathway, the free-energy barrier 19384



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was calculated to be 53.6 kcal/mol, which implies that the adamantyl group cannot thread through the altro-α-CD cavity spontaneously. This very large energetic cost stems from steric hindrances arising from the bulky adamantyl group crossing the narrow side of the altro-α-CD. Conversely, for the tumbling pathway, the PMF possesses a free-energy barrier of 16.0 kcal/ mol, much lower than that in the threading pathway. This barrier arises from disrupted hydrogen bonds at the secondary side of the CD and the unfavorable interaction of the hydroxyl groups of the altropyranose unit with the hydrophobic cavity. The stark difference between the two free-energy barriers suggests that tumbling of the altropyranose unit may constitute the most reasonable pathway for the investigated altro-α-CD derivative to form a self-inclusion structure. The results reported here provide new insights into the mechanism that underlies self-inclusion of altro-α-CD derivatives and pave the way for further investigations aimed at designing novel classes of rotaxanes based on tumbling.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

* Supporting Information S

Discussion on the suitability of the force field utilized. Structures of α-D-glucopyranose and α-D-altropyranose. Three conformers of the altropyranose unit. Analysis of the 10 ns MD simulations to explore the flexibility of α-CD and mono-altro-αCD. Calculation of the committor distributions. Time evolution of the energy of the altro-α-CD derivative in noninclusion and self-inclusion states. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 5. Snapshots of altro-α-CD at the inflection points of the PMF. (A) At ca. θ = 75°, the altropyranose unit is in a 1C4 chair conformation, and the altro-α-CD shows an elliptically shaped, distorted cavity. (B) At ca. θ = −14°, the altropyranose unit is roughly parallel to the midplane of altro-α-CD. (C) At ca. θ = −80°, a hydrogen bond is formed between O5 and O3. (D) At ca. θ = −192°, the secondary hydroxyl groups resides in the hydrophobic cavity. (E) At ca. θ = −276°, the altro-α-CD shows a cylinder-shaped cavity, and the altropyranose unit adopts a 4C1 chair conformation. For clarity, water molecules are not shown.

Corresponding Author

*(W.C.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study is supported by National Natural Science Foundation of China (No. 21373117), Natural Science Foundation of Tianjin, China (No. 13JCYBJC18800), and MOE Innovation Team (IRT13022) of China. The CINES, Montpellier, France, and NSCC, Tianjin, China, are gratefully acknowledged for provision of generous amounts of CPU time on their SGI Origin Altix and TH-1. The Cai Yuanpei program is also appreciatively acknowledged for its support of the international collaboration between the research groups of C.C. and W.C.

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REFERENCES

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Figure 6. Equilibrium structures of the altro-α-CD derivative after 30 ns MD simulations. (A) Noninclusion structure and (B) self-inclusion structure. Side view (top) and top view (bottom). Water molecules are omitted for clarity.

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Threading or Tumbling? Insight into the Self-Inclusion Mechanism of

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