Carbohydrate Research 346 (2011) 2940–2947

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Carbohydrate Research

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Molecular dynamics simulation of the dissolution process of a cellulosetriacetate-II nano-sized crystal in DMSO

Daichi Hayakawa a, Kazuyoshi Ueda a,⇑, Chihiro Yamane b, Hitomi Miyamoto b, Fumitaka Horii c

a Graduate School of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-Ku, Yokohama 240-8501, Japanb Faculty of Home Economics, Kobe Women’s University, 2-1 Aoyama, Higashisuma Suma-ku, Kobe 654-8585, Japanc Research Center for Development of Far-Infrared Region, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan

a r t i c l e i n f o

Article history:Received 12 July 2011Received in revised form 12 October 2011Accepted 12 October 2011Available online 18 October 2011

Keywords:Cellulose triacetateCTA II crystalDissolutionMolecular dynamics simulationNano-sized crystal

0008-6215/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.carres.2011.10.019

⇑ Corresponding author. Tel./fax: +81 45 339 3945.E-mail address: k-ueda@ynu.ac.jp (K. Ueda).

a b s t r a c t

An understanding of the dissolution process of cellulose derivatives is important not only for basicresearch but also for industrial purposes. We investigated the dissolution process of cellulose triacetateII (CTA II) nano-sized crystal in DMSO solvent using molecular dynamics simulations. The nano-sizedcrystal consists of 18 CTA chains. During the 9 ns simulation, it was observed that one chain (C01) locatedat the corner of the lozenge crystal was solvated by the DMSO molecules and moved away from theremaining cluster into the DMSO solvent. The analysis showed that the breakage of the interactionbetween the H1, H3, and H5 hydrogens of the pyranose ring and the acetyl carbonyl oxygen in theC01 and C02 adjacent chains would be crucial for the dissolution of CTA. The DMSO molecules solvatingaround these atoms would prevent the re-crystallization of the CTA molecules and facilitate furtherdissolution.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Cellulose is one of the most abundant and widely used materi-als. Recently, the chemical derivatives of cellulose have receivedconsiderable attention owing to their renewable and biodegrad-able properties.1 Cellulose triacetate (CTA) is one of the most com-mon cellulose derivatives, and it has been used in a variety ofcommercial products such as films and fibers for many years.2

CTA is dissolved into solvents and the resulting solutions are usedto make films and fibers in the manufacturing processes for com-mercial products. DMSO, chloroform, and dichloromethane areused as solvents in manufacturing processes and for research pur-poses.2–6 However, CTA is generally known to have poor solubilityin most solvents. Although the dissolution properties of CTA areimportant for its industrial uses, the basic solubility and solutionproperties of CTA have not been fully understood thus far; hence,further investigation is required in this regard. Recently, therehas been widespread use of CTA in new high-technology applica-tion fields such as chiral separation, medical membranes, andoptical films with highly controlled optical properties.7–9 Anunderstanding of the basic properties of the solubility of CTA isimportant in the development and design of products with newfunctionality for use in these fields. Studies of the solubility fromthe microscopic point of view are especially important for

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improvement of the dissolution process and development of newfunctionalities of CTA. There are some works in which the confor-mation and solvation of CTA in some solvents were studied.4–6

However, the molecular level behavior of the solubility and the dis-solution process have not yet been fully investigated. In this paper,we performed a molecular dynamics simulation of CTA in DMSOsolution and investigated the initial dissolution process to eluci-date the molecular behavior of the dissolution of CTA into thesolvent.

It is known that CTA has two main types of crystal structures,called CTA I and CTA II, which correspond to cellulose I and II,respectively.10,11 These crystal structures have been investigatedfor many years and several unit cell models were published. Asfor the structure of CTA II, the first structural approach was per-formed by Dulmage,12 following Roche et al. who determined thecrystal structure of CTA II from an X-ray and electron diffractiondata.11 They constructed a three-dimensional structure model ofCTA II with 18 chains, and showed that it has the same basic shapeas the experimentally obtained single crystal with micron-size.However, there was a short contact between the hydrogen atomsin the conformation at C6 acetyl residues in their CTA II crystalmodel. Zugenmaier revised the crystal structure of CTA II of Rocheet al. to remove the close contact of the hydrogen atoms in thestructure.13 For the first step of our work, we used the crystalstructure derived by Zugenmaier and made a model of the CTA IInano-sized crystal that consists of 18 chains of CTA. We investi-gated the dissolution process of this crystal in DMSO solvent usingthe method of molecular dynamics simulation.

D. Hayakawa et al. / Carbohydrate Research 346 (2011) 2940–2947 2941

2. Computational details

2.1. Nano-crystal model of CTA II and its nomenclature

The process of dissolving CTA in DMSO solvent was investigatedusing molecular dynamics simulation with a CTA II nano-sizedcrystal model. The shape of the whole structure of the CTA IInano-sized crystal model used in our simulation is shown in Figure1a. It consists of 18 chains of CTA, which were constructed accord-ing to the unit cell data obtained by Zugenmaier.13 The unit cell hasan orthorhombic structure with space group P212121, and thesize of the unit is a = 2.468 nm, b = 1.152 nm, c = 1.044 nm,a = b = c = 90�. The gross shape of the nano-crystal is similar to thatobserved in the single crystal.11 It is noted that the C01 and C02chains are oriented parallel to each other, while the C02 and C03chains exhibit an antiparallel orientation in the figure.

The structure of the nano-crystal of CTA II was minimized andused in this study as an initial structure to simulate the dissolutionprocess in the solvent. This is the maximum-sized economicalcrystal model for the conventional computer in a laboratory scalecalculation. The structure and the nomenclature of the CTA chainand the monomer unit of CTA are shown in Figure 1b and c,respectively.

All the molecular dynamics simulations were calculated usingCHARMM program version 34.14 The glucose unit was modeled usingparameters specifically developed for carbohydrates.15,16 All themolecular dynamics simulations were performed with isobaric-isothermal (NPT) ensemble with 1 fs time step. Nonbonded inter-actions were calculated using a group-based cutoff14 with aswitching function and were updated for every five time steps.The switching function was turned on at 1.2 nm and turned offat 1.35 nm. All the bonds containing hydrogen were constrainedusing the SHAKE algorithm.17 Electrostatic interaction was calculatedusing the Ewald summation method.18 The dielectric constant wasset at 1.0. The pressure was kept constant at 1 atm and thetemperature at 300 K, which was controlled by a Nose–Hooverthermostat.19,20

A thousand steps of conjugated minimization were first appliedto Zugenmaier’s nano-crystal model to relieve small strains. TheDMSO model, which was derived by Rao and Singth,21 was used.This model treats the methyl groups of DMSO as united atoms.DMSO molecules were randomly dispersed in the 8.0 � 8.0 �8.0 nm rectangular box so that the density was in agreement withthe experimental value of DMSO.22 Periodic boundary conditionswere applied to the system and the solvent box was equilibratedfor 1 ns at 300 K and 1 atm. Next, the CTA II crystal was placed atthe center of the equilibrated rectangular box of DMSO molecules.Those solvent molecules that overlapped with the CTA crystal wereremoved. The resulting system has the nano-sized crystal with 18CTA chains and 3918 DMSO molecules, the number of atoms being19614 in total. To relax the solvent molecules around the CTA crys-tal, 10 steps of Adopted Basis Newton Raphson method (ABNR) en-ergy minimization were performed by constraining all the CTAatoms. Then, 1000 steps of energy minimization with ABNR wereperformed by fixing all torsion angles (/,w) in the glycosidic link-ages of CTA. Molecular dynamics simulations were then performedto equilibrate the system over a period of 100 ps at 300 K. Duringthe equilibration process, all glycosidic torsion angles (/,w) wereagain constrained to keep the main chain conformation of the crys-tal structure unchanged. After this equilibration procedure, molec-ular dynamics simulation was performed for 9 ns without anyconstraint on the system. The trajectories were saved every 50 fsand subsequently used in the analysis. An additional trajectory ofthe molecular dynamics simulation was also computed with a dif-ferent set of initial velocity components for each atom to confirm

the result of the dissolution behavior of this work. Data visualiza-tion was done using VMD1.8.7.23

3. Results and discussion

Snapshot pictures of the CTA II nano-crystal in DMSO solventbefore and after the 9 ns simulation are shown in Figure 2. It isshown that the structure of CTA II began to dissolve into theDMSO solvent although the whole structure still maintains theoriginal shape, even after 9 ns simulation. Nevertheless, it is ob-served that the C01 chain was separate from the remaining clus-ter of the crystal and dissolved into the DMSO medium. Toconfirm that the ‘chains falling apart’ is caused by the introduc-tion of the DMSO solvents, we continued the minimization of Fig-ure 2a structure in a vacuum to reach a local minimum. It showedthat there was very little change in the cluster shape after the1000 steps minimization and the chains stick together. We alsoperformed molecular dynamics calculation in a vacuum for 9 nsand confirmed that there was no ‘falling apart’ of the chains fromthe crystal. From these results, we can conclude that the dissolu-tion of the cluster is caused by the solvation of the DMSO sol-vents. To investigate the dissolution process in detail, wefocused on the behavior of the C01 chain during the moleculardynamics simulation.

Time evolution of the interaction energy between two chains ofC01 and C02 was first investigated and the results are shown inFigure 3a. It can be seen that the interaction energy decreased withincreasing simulation time and it almost disappeared after 9 ns.During dissolution, the C01 chain should be solvated by the sur-rounding DMSO solvents. Therefore, the interaction energy be-tween the C01 and the surrounding DMSO molecules wascalculated and the result is shown in Figure 3b. The interaction en-ergy of solvation is found to increase with increasing simulationtime. The decrement of the interaction energy between the C01and C02 chains is 60 kcal/mol. In contrast, the increment of theinteraction energy between the C01 and solvent DMSO moleculesis �80 kcal/mol. As the interaction between the two chains was re-placed by the interaction of the solvents during the dissolutionprocess, this indicates that the gain of the solute–solvents interac-tion energy is larger than the loss of energy by the breakage ofchain–chain interaction. However, it should be mentioned that inorder to discuss the thermodynamics of the solvation we need toevaluate the free energy, which includes the entropy changesresponsible for solvent reconfiguration and the disordering of sol-ute chains and so on during the dissolution process. These calcula-tions are still expensive and we want to consider them in futurework.

Before analyzing the interaction between the C01 and C02chains in more detail, we investigated the original crystal structureof CTA II precisely to discover what kind of interaction works be-tween CTA chains in the crystal. In the case of cellulose, it is knownthat hydrogen bond interaction plays an important role in buildingits crystal structure.24–29 Therefore, breakage of the hydrogen bondis an important consideration in the dissolution process of cellu-lose. However, CTA has no hydrogen bond in its crystal structure.To discover what kind of interaction works in the CTA crystal,the atom pairs with short distances between their C01 and C02chains were investigated in the crystal structure of CTA II. Table1 shows such atom pairs and the distances that were found be-tween their C01 and C02 chains in the crystal. Nishio et al. exten-sively investigated the distances between the atom pairs in thecrystals of various kinds of organic molecules using the CambridgeStructural Database (CSD).30 They elucidated that several typesof weak interactions, such as CH/p and CH/O type interactions,exist in many organic crystals.31,32 They concluded that a CH/O

Figure 1. (a and b) Plane projection of the CTA-II nano sized crystal structure model. 18 chains were named from C1 to C18 as shown in the figure (a). Each CTA chain consistsof 6 residues from CT1 to CT6 (b). The nomenclature of the atoms of the monomer unit of CTA was shown in (c).

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interaction would exist when the distance between the CH hydro-gen and oxygen atoms is closer than about 0.3 nm.

CH/O pairs with distances shorter than 0.3 nm were also foundbetween the adjacent C01 and C02 chains in the CTA II crystal; theOA2 carbonyl oxygen in one chain and the H1, H3, and H5 hydro-gens in another chain. This indicates the possibility of the OA2 car-bonyl oxygen making CH/O interactions with the H1, H3, and H5hydrogens simultaneously. As these three hydrogens make the

H1–H3–H5 plane on the glucopyranose ring, the OA2 oxygen canbe considered to interact with the H1, H3, and H5 hydrogens inthe plane in an equivalent fashion. Although strong interactionssuch as hydrogen bonding do not exist in the CTA II crystal, a num-ber of weak CH/O interactions could possibly exist and work as aforce to build and stabilize the CTA crystal.

Similar inter-chain atom pairs with short distances were alsofound between three HM3 methyl hydrogens in one chain and

Figure 2. Snapshot figures of the nano-crystal of CTA-II before (a) and after the 9 ns molecular dynamics simulation (b). Co-existing DMSO molecules are not described inthese figures.

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the OA3 carbonyl oxygen in another chain, and between three HM6hydrogens in one chain and the OA6 carbonyl oxygen in anotherchain. Although their distances are slightly larger than the criteriafor interaction distance, these pairs can still possibly make aninteraction during the thermal fluctuation of the crystal. Theseinteractions were schematically shown in Figure 4.

The time dependence of the distances between the atom pairslisted in Table 1 was investigated in our simulation. The resultsare shown in Figure 5. The distances were calculated separatelyin each residue of the hexamer chain. The distances for all atompairs were found to increase in all residues with increasing simu-lation time. This shows the disappearance of the interactions be-tween the chains for the duration of the simulation. Among allatom pairs, the distance between OA2 and H1–H3–H5 (redlines)� increases most slowly with the simulation time. This indi-cates that the breakage of the interaction between OA2 and H1–H3–H5 would be the most important factor when the CTA is dis-solved in DMSO.

The time course of the interactions between HM3 and OA3(blue line) shows almost similar behavior to that between OA2and H1–H3–H5, but their interaction disappeared somewhat ear-lier than that associated with OA2. On the other hand, the interac-tion between HM6 and OA6 (green line) was found to disappeareven in the initial stage of the simulation (green lines). As the acet-yl group at 6th position orients toward the outer side from theremaining crystal, it is easily subjected to attack by the DMSO mol-

� For interpretation of the references to colour in this figure legend, the reader isreferred to the web version of this article.

ecules and this results in the rapid disappearance of the directinteraction between the chains.

Figure 2b shows that the C18 chain is also beginning to separatefrom the C17 chain and is dissolving into the solvents. Althoughthis chain pair is symmetrically equivalent to the C01 and C02 pair,a slight variation of environment of the respective chains may leadto different dissolution behaviors of the C17 and C18 chains. There-fore, the interaction behavior between the C17 and C18 chains wasexamined in a similar fashion to those of the former two chains.The results are shown in Figure S1 as Supplementary data. The dis-solution behavior is found to be almost the same with the C01 andC02 chains. That is, the pair of HM6 and OA6 separates in the earlystage of the simulation, and OA2–(H1,H3,H5) and OA3-HM3 pairs,especially OA2–(H1,H3,H5) pair resists dissolution. We also per-formed an additional molecular dynamics simulation, which wasstarted using different initial velocities of the CTA atoms. In thiscase, it is observed that the pair of C17 and C18 chains dissolvedearlier than the C01 and C02 chains. This shows that the chanceof dissolution in both edges is equal from a statistical point of view,that is, a slight variation of environment of the solvent orientationsaround the CTA cluster affects the starting of the dissolution. Theinteraction behavior between C17 and C18 chains was examinedin the same way and the results are shown in Figure S2 as Supple-mentary data. It also shows that the dissolution behavior is almostthe same as with the previous trajectory. That is, the distance be-tween OA2 and H1–H3–H5 increases most slowly with the simula-tion time among all atom pairs.

The time of the disappearance of the interaction differs fromresidue to residue. The interaction begins to disappear from the

Figure 3. Time courses of the interaction energy between the C01 and C02 chains in the CTA II nano-cluster (a) and between the C01 chain and the DMSO molecules (b).

Table 1Atom pairs with short distances between the C01 and C02 chains in the crystalstructure of CTA II13 are listed

Atom pair Distance/nm

OA2 H1 0.247OA2 H3 0.289OA2 H5 0.272Average 0.269

HM3 OA3 0.420HM3 OA3 0.410HM3 OA3 0.317Average 0.382

HM6 OA6 0.286HM6 OA6 0.372HM6 OA6 0.416Average 0.358

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end of the chain that is surrounded with more DMSO molecules. Ifwe roughly set the threshold value of the distance of the disap-pearance of the interaction between the chains at around 0.5 nm,we can estimate the time of the breakage of interaction betweenthe chains by observing the timeline of the distances between

the OA2 and H1–H3–H5 pairs. In the initial stage, the CT1 residueswere unpaired at around 1 ns and then the CT2 and CT6 residues ofC01 were separated from the C02 chain at around 3 ns. Finally, theCT3, CT4 and CT5 residues were separated from the crystal ataround 6 ns. Therefore, we roughly estimate that it takes 2–3 nsfor one residue to separate from the remaining CTA. From thisbehavior, we can roughly estimate the dissolution time of onechain of commercially manufactured CTA from the remaining bulkcrystal. As the degree of polymerization of such CTA is about 200–400, we can roughly estimate the rate of dissolution as 0.4–1.2 lsper chain from this simulation.

3.1. Time dependence of the number of solvent moleculeswithin the first solvation shell

When the crystal of CTA dissolves into the solvent, breakageof the interacting atom pairs of CTA should accompany the sol-vation of the surrounding DMSO molecules. To analyze the sol-vation behavior, we evaluated the number of solvent moleculesaround some selected atom sites in the C01 chain. In the previ-ous section, we found three types of atom pairs, OA2–(H1–H3–

Figure 4. Schematic representation of the interaction between the C01 and C02 chains in the CTA II crystal. For simplicity, only the interaction sites of the CT1 residues in theC01 and C02 chains are shown in the figure.

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H5), HM3–OA3, and HM6–OA6, which are formed between theC01 and C02 chains. As two H1–H3–H5 and H2–H4 sides ofthe glucopyranose ring appear alternatively along the 2/1 helicalCTA chain, we selected 3 atom sites of OA2, CM3, and CM6 inthe CT1, CT3, and CT5 residues and also 3 atom sites of H1–H3–H5, OA3, and OA6 in the CT2, CT4, and CT6 residues. Here,CM3 and CM6 are the acetyl methyl carbons where HM3 andHM6 connected, respectively. Previously, we reported the radialdistribution function of DMSO molecules around some atomsof the acetyl group of the CTA single chain.33 It showed thatthe radius of the first solvation shell of DMSO molecules aroundthe acetyl methyl carbon is about 0.45 nm.33 To investigate thetime dependence of the solvation process, the change in thenumbers of the DMSO molecules in the first solvation shellaround the selected atom sites was analyzed. Figure 6 showsthe results calculated for the respective residues of the C01 chainin the CTA II crystal. The general behavior of the solvation is al-most similar to that of the interaction distance change shown inFigure 5. The acetyl group at 6 position (CM6, OA6; green lines)is well solvated even in the condition before dissolution. Thenumber of DMSO molecules around the OA6 (green lines inFig. 6b, d, and f) is about 3 and the number around the CM6(green lines in Fig. 6a, c, and e) is 2.5 during the entire simula-tion time.

On the other hand, H1–H3–H5 and OA2 (both are red lines)hardly interact with DMSO molecules at the initial stage of thesimulation, but the number of solvated molecules gradually in-creases at these sites. Figure 6c shows the solvation behavior atthe central residue of the C01 chain, where one DMSO molecule be-gan to approach the OA2 atom site at around 1.5–6 ns. During thisperiod, the interaction distance was slightly increased and fluctu-ated, as is seen in Figure 5c. However, the interaction betweenthe pair atoms in the central residues was still maintained. After6 ns, the number of solvated molecules increased to 3 and thenthe interaction between the pair atoms was disconnected. Figure6e also shows similar behavior: one DMSO molecule solvated in3.5–6.0 ns and then the number of solvated molecules increasedto 3. These results indicate that the solvation of the OA2 proceedswith two steps. Namely, one DMSO molecule first solvates andloses the interaction between the pair atoms. Next, full solvationwith three DMSO molecules occurs and the interaction betweenthe atom pairs disappears.

The solvation around the OA3–CM3 pair (blue lines) shows theintermediate behavior between the case of OA2–(H1–H3–H5) andthe case of OA6–CM6. From all these results, it is noted that thebreakage of the interaction between OA2–(H1–H3–H5) by the sol-vation is a controlling factor of the dissolution of CTA in DMSO.

3.2. Conformational change of the main chain of CTA during thedissolution

It is interesting to know the conformational change of the C01chain during the dissolution process. We examined the time courseof the main chain conformation by investigating the order of orien-tation of the pyranose rings in the chain. For this purpose, thedirection of the normal vector for each pyranose ring’s planar sur-face was defined by the cross product of C1 to C3 and C1 to C5 vec-tors. The rotational distortion of the angles between two pyranosering planar surfaces of the adjacent residues was calculated fromthe dot products of these normal vectors, as is shown in Figure7a. The time courses of the angles obtained for three adjacent res-idue pairs are shown in Figure 7b. It should be mentioned that thevector angles are the results of the variation in the u and w glyco-sidic torsion angles and possible ring puckering in the chain con-formation. As these data are the basic information in the analysisof the chain conformation, they were also analyzed for the C01chain, and the obtained time courses of u, w glycosidic torsion an-gles and the Cremer–Pople ring puckering parameter H34 areshown in Figures S3 and S4 as Supplementary data, respectively.The value of ring puckering parameter H indicates that all the glu-copyranose rings well keep the 4C1 chair conformation in all timesduring the simulation.

As a reference, the angle (180�) calculated for the 2/1 helicalchain in the original CTA II crystal is also shown in the figure.Although the angles between the CT4 and CT5 residues rapidlydecreased to 160� from the value in the crystal at the initial stageof the simulation, the deviation is still small and the planar struc-ture may almost be maintained. However, a twisted helical struc-ture with a value of around 130� seems to appear after 6 ns. Thetime of this conformational change coincides with the time forthe change of the interaction distance of OA2–(H1–H3–H5) andHM3–O3 found in Figure 5d and e. This indicates that the break-age of the interactions of OA2–(H1–H3–H5) and HM3–O3 be-tween the C01 and C02 chains and the distortion of the chainconformation occur simultaneously. Namely, the breakage of theCH/O interactions of OA2–(H1–H3–H5) and HM3–O3 accompa-nies the disruption of the planar structure of the glucopyranosechain and it changes conformation to the twisted helicalstructure.

The angle between the CT2 and CT3 residues was graduallyreduced at 1–5 ns. This is again synchronized with the behaviorof the interaction distance changes shown in Figure 5b and c. Onthe other hand, the angle between CT3 and CT4 was found to bedistorted from the beginning. This is explained by the differentbehaviors of the interaction found in the groups of CT2–CT3

Figure 5. Time courses of the distances of the atom pairs between the C01 and C02chains in the CTA II crystal. They were calculated for each residue from CT1 (a) toCT6 (f). In (a), (c) and (e), the red lines indicate the average distance between theOA2 oxygen in C01 and the H1–H3–H5 hydrogens in C02; The blue lines indicatethe average distance between the three HM3 methyl hydrogens in C01 and OA3 inC02; The green lines indicate the average distance between the three HM6hydrogens in C01and OA6 in C02. In (b), (d), (f), red lines: H1-H3-H5 in C01 and OA2in C02; blue lines: OA3 in C01 and HM3 in C02; green lines: OA6 in C01 and HM6 inC02. s (red), 4 (blue), h (green) show the initial distance of the crystal structure13

shown in Table 1. (For interpretation of the references to colour in this figurelegend, the reader is referred to the web version of this article.)

Figure 6. Time courses of the number of DMSO molecules that exist within the firstsolvation shell (r <0.45 nm) around the selected atom sites in the C01 chain of theCTA II crystal. The atom sites selected for the CT1 (a), CT3 (c), and CT5 (e) residuesare OA2 (red line), CM3 (blue line), and CM6 (green line). Similarly, the atom sitesselected for CT2 (b), CT4 (d), and CT6 (e) are H1-H3-H5 (red line), OA3 (blue line),and OA6 (green line). The number of solvated DMSO molecules around H1–H3–H5was the average of the number obtained for each hydrogen of H1, H3 and H5. (Forinterpretation of the references to colour in this figure legend, the reader is referredto the web version of this article.)

2946 D. Hayakawa et al. / Carbohydrate Research 346 (2011) 2940–2947

Figure 7. Time courses of the angles between the pyranose ring planers of theadjacent residues of the C01 chain during the dissolution process. The definitionand the notation of the angles are shown in (a). The angles between the adjacentresidues of CT2–CT3, CT3–CT4, and CT4–CT5 are shown in (b).

D. Hayakawa et al. / Carbohydrate Research 346 (2011) 2940–2947 2947

(Fig. 5b and c) and CT4–CT5 (Fig. 5d and e). Namely, the inter-action of these two groups changed between CT3 and CT4.

In the crystal structure, the C01 and C02 chains are aligned par-allel to each other. The interaction between the OA2 and H1–H3–H5 would play an important role to stabilize the planarity of theCTA chains in the crystal structure. However, for a single strandCTA molecule, the helical structure is more stable than the planarstructure of 2/1 helix. Buchanan et al. suggested that the CTA existsas 5/4 helix in chloroform from the NMR experiment.6 Our previ-ous molecular dynamics simulation has shown that a single chainCTA takes 3/2 helix in DMSO solvent.33 Moreover, the crystal struc-tures of fully acetylated dimer and tetramer molecules show thesame glycosidic torsion angles of the CTA in 3/2 helix.35,36 These re-sults suggest that the CTA chain would undergo the conformationalchange to a helical structure when the CTA molecule detaches fromthe remaining cluster into the solvent. It would be difficult toreconstruct the original planar structure once the CTA chain wasdissolved in the solution. Thus, the DMSO molecules solvatingaround the CTA and the conformational change of the CTA mainchain would prevent the re-crystallization of the CTA moleculesand help the further progress of the dissolution.

4. Conclusions

Three types of interaction sites were found between the adja-cent CTA chains in the CTA II crystal. The strongest interaction ex-ists between the H1, H3, and H5 hydrogens of the glucopyranosering and the OA2 acetyl carbonyl oxygen (at position 2 in the glu-cose residue) in the adjacent C01 and C02 chains. A secondarystrong interaction site was found between the OA3 acetyl carbonyloxygen and the acetyl methyl hydrogens (HM3) in the acetyl groupat position 3 in the adjacent C01 and C02 chains. The third is theinteraction between the OA6 acetyl carbonyl oxygen in one chainand the acetyl methyl hydrogens (HM6) at position 6 in anotherchain. These interactions may be considered to categorize the weakhydrogen bond between the CH hydrogens and O atoms, althoughthere is still controversy about the existence of a weak C–H� � �O

type hydrogen bond interaction. In the dissolution process, theseinteractions were reduced to zero in their specific ways and theinteracting atoms were surrounded by the DMSO molecules. Theanalysis of the time course of the interactions and the number ofsolvating DMSO molecules within the first solvation shell indicatethat the interactions between OA2 and H1–H3–H5 and betweenOA3 and HM3 are important factors to resist the CTA to dissolveinto the DMSO solvent. Of these two interactions, the OA2 andH1–H3–H5 interaction is the most important in the dissolutionprocess. The solvation of DMSO molecules and the conformationalchange of the CTA main chain would contribute to the dissolutionas an entropic effect and, therefore, recrystallization of the CTAmolecules is difficult once dissolved.

Acknowledgments

The authors wish to thank the Research Center for Computa-tional Science, Okazaki, Japan for the use of their computer toperform part of the calculation. This work was supported byGrants-in-Aid for Scientific Research (No. 22500272) from the Min-istry of Education, Culture, Sports, Science and Technology ofJapan.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.carres.2011.10.019.

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