Molecular mechanics study ofb-cyclodextrin 6-O-monobenzoateinclusion complexes

Ping Jiang, Hong-Wei Sun, Rong-Xin Shen, Jing Shi, Cheng-Ming Lai*

Department of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China

Received 26 August 1999; received in revised form 23 November 1999; accepted 23 November 1999

Abstract

Calculations have been done onb-cyclodextrin 6-O-monobenzoate and its complexes using molecular mechanics MM2force field. The guest molecules involved weren-hexane,n-heptane,n-octane, cyclohexane, methylcyclohexane, cyclooctaneand methylcyclooctane. Owing to lack of dipole–dipole and hydrogen-bonding interactions in the inclusion complexation ofthe modified cyclodextrin, the calculations of the geometry of the complexes and the inclusion process indicated that thecomplex formation is stabilized by van der Waals interaction. The energy differences of the modified cyclodextrins bycalculation show that the size, shape, conformation of the guest molecules play significant roles in the inclusion complexation.q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Modified cyclodextrins; Molecular mechanics; Host–guest interaction; Inclusion complexes

1. Introduction

Cyclodextrins (CDs) are seductive molecules,appealing to investigators in both pure research andapplied technologies. They serve as hosts for a varietyof small molecules, in aqueous and organic solutions[1–3]. They have found use in many fields such aschromatography, the pharmaceutical industry, foodtechnology, biotechnology, cosmetics and catalysis.Cyclodextrins can also be regarded as enzyme mimics[4–6]. In recent years, they have been subjected todiverse modifications to give wide variety of CD deri-vatives [7–9]. A variety of cyclodextrin derivativeshave hitherto been synthesized in order to modify orenhance the original molecular recognition propertiesof the native cyclodextrins. These modified cyclodex-trins have widely been employed, for example, as

enzyme mimics, supramolecular receptors and chiralselectors in separation science and technology [10].

Recently, there has been considerable interest in thecomputer modeling of cyclodextrins [11–15]. Mostcomputational studies of cyclodextrins involvehost–guest complexes. Their shapes, energies,preferred binding orientations and so on are typicallycomputed. Molecular mechanics (MM) [16–26] andmore recently molecular dynamics (MD) [27–33]calculations are useful for a better understanding ofsuch inclusion processes of cyclodextrins. The calcu-lations can strengthen and supplement the conclusionsfrom experiment, and vice versa. However, most ofthese research work have focused on the host–guestcomplexes of natural cyclodextrins [16–26] and fewhave been concerned with the modified cyclodextrinsso far [34].

In this paper, we have applied molecular mechanics(MM) to try to study a modifiedb-cyclodextrin carry-ing one chromophoric benzoate moiety. In order to

Journal of Molecular Structure (Theochem) 528 (2000) 211–217

0166-1280/00/$ - see front matterq 2000 Elsevier Science B.V. All rights reserved.PII: S0166-1280(99)00492-3

www.elsevier.nl/locate/theochem

* Corresponding author. Fax:186-235-02458.E-mail address:chemcz@sun.nankai.edu.cn (C.-M. Lai).

provide further insight into the interactions betweenhost and the guests, the inclusion processes, thegeometry of the complexes and the energy differencesare computed. This provided the significance of modi-fied cyclodextrins in molecular recognition.

2. Computational details

The calculations were carried out with a modifiedversion of Allinger’s MM2 force field and made in theabsence of solvent. This force field approximates thepotential energy function of a molecule as the sum of

terms for bond stretching, angle bending, torsion, vander Waals and electrostatic interactions.

The startingb-cyclodextrin structure for the simu-lation was taken from the published neutron diffrac-tion data [35]. Then the monobenzoate was added atthe 6-position of cyclodextrins according to the litera-ture [36] and the geometry was fully optimized usingMM2 force field. Fig. 1 shows the structure of the hostmolecule. Guest molecules,n-hexane,n-heptane,n-octane, cyclohexane, methylcyclohexane (two orien-tations for inclusion process), cyclooctane andmethylcyclooctane, were minimized using the AM1semi-empirical method ofmopac 97. One conformerof each guest was mainly discussed in this paperaccording to the literature [25]. Acyclic and cyclichydrocarbon guest molecules are employed so as tominimize the possible participation of electrostaticand hydrogen-binding interactions. All the optimizedstructures were considered the initial geometry in thecalculation of inclusion processes.

The coordinate system used to define the process ofcomplexation is shown in Fig. 2. The method wascarried out referring to the work of the group ofJaime [24,25]. For the complexation process, thehost is kept in this position while the guest approachesalong theZ-axis toward the wider edge of the hosttorus. The guests was initially located at aZ-coordi-nate of214 A and was moved through the host cavityalong theZ-axis to 114 A in steps of 1 A˚ . At eachstep, the entire structure was optimized without anyrestriction. In order to find an even more stablestructure of the complex, each guest molecule was

P. Jiang et al. / Journal of Molecular Structure (Theochem) 528 (2000) 211–217212

Fig. 1. The structure ofb-cyclodextrin 6-O-monobenzoate. Hydro-gen atoms are not drawn for the sake of clarity.

OO

Z

X

Y

C1

C2

C3

C4

C5

C6

O

Fig. 2. Coordinate system used to define the process of complexation.

P.

Jian

ge

ta

l./

Jou

rna

lof

Mo

lecu

lar

Stru

cture

(Th

eo

che

m)

52

8(2

00

0)

21

1–

21

7213

Fig. 3. Three-dimensional plot of the steric energy versusu and the distance (Z, in A) between the host and hexane.

calculated for all of the structures obtained by scan-ningu at 208 intervals from 08 to 1808 circling aroundZ-axis and scanningZ-coordinate at 1 A˚ intervalsfrom 214 to 114 A.

3. Results and discussion

When the guest molecule approaches the host, theenergy of the system begins to decrease. Once insidethe cavity there is a range of positions that it canassume with rather close energy values. Moving itdeeper inside and away from the cavity, the energyagain increases, almost reaching an initial value. Nomatter where the initial position of the guest was, itshows the same trend. As an example, Fig. 3 depictsthe three-dimensional plots of the total steric energyversusu and Z-coordinate for hexane and the host.The energy minimum structures of all the complexeswere obtained by using this method.

The total steric energies of the energy minimumstructures of the complexes, as well as several compo-nents, are depicted in Table 1. It has been noted thatthe van der Waals interactions contribute most of thestabilization in the complexes. In fact, the real drivingforces for the inclusion complexation of the CDs andthe guest molecule depend on the intermolecularinteractions of the host and the guest. Due to thenon-polar character of our guests, van der Waals inter-actions seems to be responsible for the final geometry.

Lacking any site-specific dipole–dipole and hydro-gen-bonding interactions between host and hydrocar-bon guests, the modified cyclodextrin appears torecognize the guest molecule predominantly throughits molecular size and shape, maximizing hydropho-bic interaction within the host cavity. As a result, thesize-fit, or shape-fit, relationship between host andguest molecules becomes the major factor governingthe complex stability. For this purpose,DE was calcu-lated for the minimum energy structures.DE stands

P. Jiang et al. / Journal of Molecular Structure (Theochem) 528 (2000) 211–217214

Table 1The energies of all the most stable complexes (kcal mol21)

Guest Stretch Bend Stretch–bend Torsion Non-1,4-VDW 1,4-VDW Dipole/dipole Total

Hexane 8.5651 49.1607 4.6788 27.0568270.3807 98.9852 213.2624 104.8034Heptane 8.5544 49.2987 4.6486 26.9215272.2099 100.0921 213.6155 103.6899Octane 8.7288 49.2222 4.7361 26.9499274.0056 100.2616 213.3495 102.5436Cyclohexane 8.7916 49.4511 4.7818 29.3795272.5279 99.9045 213.4740 106.3064Methylcyclohexane-1a 8.7752 49.4948 4.7587 28.6699 274.0272 100.1824 212.5431 105.3107Methylcyclohexane-2b 8.8495 49.1935 4.7806 29.4116 273.4183 100.5165 213.5218 105.8116Cyclooctane 9.4008 53.2999 5.1766 37.1577277.1245 102.5967 214.4559 116.0513Methylcyclooctanec 9.2492 53.5641 5.0882 35.3101 279.2180 102.9721 211.9814 114.9845

a The cyclohexane group is first included into the cavity.b The methyl group is first included into the cavity.c The methyl group is first included into the cavity.

Table 2The steric energy differences (DE) between the host and the guest.DDE is the energy difference between the twoDE (kcal mol21)

Guest HostModifiedb-CDs (DE) Naturalb-CDs (DE) DDE

Hexane 216.7749 214.8482 21.9267Heptane 218.4704 216.1171 22.3533Octane 219.5902 217.8253 21.7649Cyclohexane 218.4225 216.6945 21.7280Methylcyclohexane-1 220.2098 218.2530 21.9568Methylcyclohexane-2 219.3476 217.2500 22.0976Cyclooctane 222.3265 222.0615 20.2650Methylcyclooctane 225.4152 222.6762 22.7390

for the steric energy difference between the complexand the total of isolated host and isolated guest. Itsrepresentation can be written as following:

DE � Ecomplex2 �Eisolated host1 Eisolated guest� �1�Table 2 shows the results of the calculations.

From the data collected in Table 2, it can be seen

that the steric energy change (DE) increases withincreasing chain-length or ring-size in all of the calcu-lated cases of alkane, cycloalkane series.DE standsfor the intermolecular interactions which is almost allof the non-bonded van der Waals interactions betweenthe host and the guest. With the increase of the chain

P. Jiang et al. / Journal of Molecular Structure (Theochem) 528 (2000) 211–217 215

-15 -10 -5 0 5 10 15100

105

110

115

120

125

ster

ic e

nerg

y(kc

al/m

ol)

z coordinate(Å)

(a)

-15 -10 -5 0 5 10 15100

105

110

115

120

125

ster

ic e

nerg

y(kc

al/m

ol)

z coordinate(Å)

(b)

-15 -10 -5 0 5 10 15100

105

110

115

120

125

130

ster

ic e

nerg

y(kc

al/m

ol)

z coordinate(Å)

(c)

Fig. 4. The total steric energy variation for the inclusion of hexane,heptane and octane into the host versusZ coordinate (A˚ ): (a)u � 808; (b) u � 1008 and (c)u � 808, respectively.

(a)

(b)

(c)

Fig. 5. MM2 computed energy minimum structures for: (a) hexane,(b) heptane and (c) octane. Hydrogen atoms are not drawn for thesake of clarity.

length or ring size of the guest, the van der Waalsinteractions sites are increased and strengthened. Ascan be also seen from Table 2, it seems reasonable topropose that octane and methylcyclooctane are moresuitable for the host than the other guests. Further-more, the modified cyclodextrins also seem to showbetter complexing behavior than unmodified cyclo-dextrins and hold greater potential in the formulationof complexes.

In order to provide further insight into it, we calcu-lated the steric energy differences (DE) between thenaturalb-cyclodextrin and the same guests. TheDDE,which is theDE differences of the same guest mole-cules between the modifiedb-CDs and the naturalb-CDs, was also calculated. Table 2 contains the results.

From the data in Table 2, it can be also seen thatDEof the naturalb-cyclodextrin increases with increas-ing chain-length or ring-size. However, compared

with DE of modified b-cyclodextrin, the values arelower about 0.26 to 2.74 kcal mol21. Hence, thebenzoate moiety as a probe, located on the edge ofthe cyclodextrin cavity, seems to enhance the interac-tions and can recognize minimal differences betweenhydrocarbons based on their size, rigidity and shape. Itcan be also shown by the geometry and the energychange in the course of inclusion.

As an example, Fig. 4 depicts the steric energyvariation of the inclusion process of hexane, heptaneand octane into modifiedb-CDs atu � 808; u � 1008and u � 808; respectively. The energy variationinvolved in the inclusion emulation indicates thatthe complexes prefer to adopt an inclusion geometrywith the guest inside the host cavity in order toincrease the van der Waals attraction. Fig. 5 showstheir energy minimum structures, which can be expli-citly understood that octane fits the host in size betterthan that of the two others.

It can be also noted that two different orientationsof methylcyclohexane have been considered for thecalculations. Methylcyclohexane-1 means cyclohex-ane group is first included into the host cavity; methyl-cyclohexane-2 means methyl group is first.Comparing theirDE values in Table 2, it can beseen that methylcyclohexane-1 seems to be morestable. Because it has much more interaction sites inthe host cavity and enhance van der Waals interac-tions. Fig. 6 shows their structures. It indicates that thecyclohexane has the larger possible number of atomsinside the cavity. As for methylcyclooctane, when thecyclooctane group is first included into the cavity,because of having the methyl group, the guest mole-cule is too large to embed the host too much and theirinteractions are lower in our tentative calculations. Soonly one orientation of the inclusion process wasdiscussed. Hence, the size or the shape of the guestmolecule is playing an important role in the inclusionprocess and molecular recognition.

4. Conclusions

The more stable structures and the inclusionprocess forb-cyclodextrin 6-O-monobenzoate inclu-sion complexes were studied by means of molecularmechanics (MM2). The driving forces for complexa-tion are dominated by non-bonded van der Waals

P. Jiang et al. / Journal of Molecular Structure (Theochem) 528 (2000) 211–217216

(a)

(b)

Fig. 6. MM2 computed energy minimum structures of methylcyclo-hexane-1 and methylcyclohexane-2. Hydrogen atoms are not drawnfor the sake of clarity.

interaction between the host and the guest. The calcu-lations of the energy differences for the complexesindicates that the modified cyclodextrin with a singlebenzoate moiety as a probe can recognize minimaldifferences between the host and the guest. And themolecular size and shape of the guests are a crucialfactors in the inclusion and the molecular recognition.In the present study, the solvent effect is not yet takeninto account and this effect sometimes influence theinteraction of the host and guest. The further elabora-tion of MD simulation is now performing.

Acknowledgements

We are grateful to Prof. Carlos Jaime, Professor ofFacultat de Cie`ncies Universitat Auto`noma de Barce-lona, for his useful discussion. Financial support wasobtained from the Research Fund for the DoctoralProgram of Higher Education (China).

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