PRL 96, 228303 (2006)

PHYSICAL REVIEW LETTERS

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Single Molecular Anatomy of Solvophobic Effects in Host-Guest Interactions Basedon Surface Tension Using Atomic Force Microscopy
Satoshi Yasuda,1 Iwao Suzuki,2 Ken-ichi Shinohara,3 and Hidemi Shigekawa1,*
1

Institute of Applied Physics, 21st Century COE, CREST (JST), University of Tsukuba, Tsukuba, Ibaraki 305-8573, Japan
2
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan3
School of Materials Science, Japan Advanced Institute of Science and Technology, Nomi, Ishikawa 923-1292, Japan(Received 20 September 2005; published 8 June 2006)
The effectiveness of the mechanism of surface tension to analyze the host-guest interaction wasdemonstrated by measuring the unbinding force of the -Cyclodextrin (CyD)—adamantane molecules ina liquid environment at the single-molecule level. The contribution of the solvophobic effect wasquantitatively distinguished from the intrinsic van der Waals force, and the effective length that produces
the detected force through employing the notion of surface tension was determined to be 1:07  0:13 nm,
which is consistent with the perimeter of the adamantane molecule, 1:3 nm. Specific strong interactionof water molecules was also confirmed on the nanoscale.
DOI: 10.1103/PhysRevLett.96.228303

PACS numbers: 82.65.+r, 82.33.z

A barberpole or a sailboat floating on water, capillaryaction, formation of droplets, and soap bubbles: these arefamiliar sights in our daily life. Behind these immediatesurroundings is surface tension. Surface tension has a 200year-old scientific history since its basis was first presented
by T. Young in 1805 [1]. The concept of ‘‘surface tension’’
was introduced and defined in the paper as the force acting
on a hypothetical line of unit length arbitrarily drawn on
the surface of a liquid. With the development of analyticaltechniques in quantum optics and surface science, thisconcept has been applied to the understanding of physicaland chemical properties at even down to the nanoscale. For
example, formation of gas phase clusters and the dynamics
of thin film growth have been extensively studied andunderstood, generating surface tension arguments. Fine
control of nanometer sized structures known as quantum
dots based on such results, for instance, is one of the keys
to current science and technology [2].
In this Letter, we demonstrate the effectiveness of employing the notion of surface tension for the analysis of ahost-guest interaction system in a liquid. Host-guest chemistry is another key to the future of nanotechnology andbiotechnology applications, and its recent progress is remarkable [3,4]. However, the detailed design of host-guest
systems, which exhibits desired functions in predetermined
structures, has not yet been successful. The most criticalpoint is that the processes include complicated many-bodyeffects arising from solvent-related factors. Since mostimportant systems are effective in a liquid, interactions
arising from solvent-related factors, such as the solvophobic effect, play important roles in intermolecular dynamics
in addition to intrinsic forces such as van der Waals (vdW)
interaction and hydrogen bonding [5–7]. Therefore, agreater understanding of the influence of the solvent effectupon the stability or association of a complex system isvery important to realize the desired host-guest systems.
With the development of atomic force microscopy(AFM) [8], it is possible to directly measure the interac0031-9007=06=96(22)=228303(4)tions between individual molecules at the pico-Newton
level [9–20]. Using this technique, we show the first direct
evidence that the mechanism of the surface tension works
in the host-guest system at the single-molecule level. We
have succeeded in distinguishing the solvophobic effect in
the host-guest interaction from the intrinsic vdW force atthe single-molecule level. The specific force of water due
to hydrogen bonding is also shown to be effective on thenanoscale.
Placed on the water surface in a glass, aluminum coins
sink when their weight exceeds the force produced by thesurface tension of the water. The maximum weight thatbreaks the force balance can be related to surface tension.
For the analysis of a similar experiment on the nanoscale,
we adopted a host-guest molecular system, a combination of -cyclodextrin (-CyD) and adamantane molecules. -CyD is a doughnut-shaped oligosaccharide consisting of seven glucose units linked in a cyclic form
[Fig. 1(a)] and forms an inclusion complex with an adamantane molecule. The inside and outside diameters of
-CyD molecule are 0.7 nm and 1.5 nm, respectively [3,4].
Therefore, the measurement of the unbinding force of thecomplex in a liquid environment enables us to analyze thesurface tension of a solvent on the nanoscale. Namely, if
the included admantane molecule is pulled out of the CyD
cavity in a liquid environment, the detected unbinding
force can be related to the surface tension of the liquid
similarly seen in the case of the aluminum coins mentioned
above.
Since the binding force of this system (-CyD andadamantane molecules) arises from the vdW and hydrophobic interactions and is free from hydrogen bonding [21]and charge transfer, the analysis of force-measurement
results is simple and reliable. This host-guest system isalso an excellent model for the understanding of the solvophobic effect in the protein-ligand enzyme interactions
because its association constant is similar to those of many
protein-ligand systems [22].

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PHYSICAL REVIEW LETTERS

0.1nN

Adhesion force(a)F
Retraction

1nm

Tip displacement
(c)

20

30

40

Auto correlation (a.u.)(b)CountsTo determine the binding force between individual
-CyD and adamantane molecules, the adhesion force
between an AFM cantilever functionalized using adamantane and self-assembled monolayers (SAMs) of -CyD
was measured and analyzed. To form the SAMs of
-CyD molecules on a Au(111) surface, we usedLP–-CyD molecules, which are -CyD molecules modified with a lipoamide residue chemically bound to theprimary hydroxyl side. The quality of the structure of thedensely packed homogeneous LP–-CyD monolayer on
the Au(111) surface was examined and confirmed using
scanning tunneling microscopy and cyclic voltammogrammeasurements [23,24]. The adamantane molecules werechemically bonded (tethered) on a gold-coated Si3 N4 AFM
cantilever using 10-adamantanyloxydecane-1-thiol molecules, which are adamantane molecules modified with anoctanethiol chemically added to one adamantyl group. The
schematics of the modified molecules and the experimental
conformations of the molecules are shown in Figs. 1(b) and
1(c), respectively.
For the analysis of surface tension on the nanoscale,binding-force measurement was performed in methanolwater solutions of various volume ratios. The solutions
with different volume ratios provide different surface tensions. The relationship between the surface tension and thevolume ratio of the methanol-water solutions in Fig. 1(d) is
determined by macroscopic measurement [25].

10

FIG. 1 (color). Structures of (a) -cyclodextrin (CyD),(b) LP–-CyD and 10-adamantanyloxydecane-1-thiol molecules, and (c) schematic illustration of experimental conformation. (d) Relationship between surface tension and volume ratioof methanol-water solutions.

A noteworthy point is that the macroscopically obtained
surface tension of water is larger than that expected fromthe linear relationship from the mix ratio of the methanolwater solutions. This is because water molecules form a
specific network structure that is considered to induce anadditional effect. The network has been analyzed macroscopically and recognized as the reason for the high surface
tension, high specific heat, and high evaporation heat ofwater. Whether this structure is on the nanoscale or not isanother interesting issue that should be resolved.
Figure 2(a) shows the typical force curve obtained.
Unbinding events occurred step by step, as shown in
Fig. 2(a). This is because the tip-sample bonding consistsof several individual host-guest bondings. For the analysisof the host-guest interaction, the pull-off force in the final
step, indicated by ‘‘F’’ in Fig. 2(a), was recorded. Morethan 300 force measurements were performed for eachsolvent. A histogram of the pull-off forces measured forwater is shown in Fig. 2(b). As indicated by arrows, there
exists a certain periodic feature in the histogram, which ismore clearly confirmed using the autocorrelation analysisof the histogram, as shown in Fig. 2(c) [26,27]. This result
indicates that the obtained pull-off forces are composed ofinteger multiples of an elementary force for unbinding asingle -CyD–adamantane complex, which is determined
to be 97  12 pN in the present case. This value is close tothat obtained in the previous work, 102  15 pN [17].
Through a similar procedure, the unbinding forces in all
solutions were determined. The measurement error (12%)
mainly arises from that in the calibration of the spring
constant of the cantilevers [28].

0PRL 96, 228303 (2006)

0 0.1 0.2 0.3 0.4 0.5 0.6

0 0.1 0.2 0.3 0.4 0.5 0.6

Adhesion force (nN)

Adhesion force (nN)

FIG. 2. (a) Typical force curve obtained for water.
(b) Histogram derived from the force measurement in water,and (c) autocorrelation analysis of histogram shown in (b).

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PHYSICAL REVIEW LETTERSPRL 96, 228303 (2006)

Figure 3(a) shows the obtained unbinding force plotted
as a function of the surface tension of the solvent, which
was determined by a macroscopic method [Fig. 1(d)] [25].
The relationship between the unbinding force and thesurface tension could be indicative of parameters such as
intermolecular interaction forces. To reduce the effect of
the complicated interactions, the host-guest system waschosen, as mentioned before, because the binding force
arises from the vdW and hydrophobic interactions and is
free from hydrogen bonding and charge transfer.
Therefore, the detected unbinding force is related to thesurface tension of the liquid, the solvent-solvent
interaction.
As presented in Fig. 3(a), the unbinding force linearly increases with the increasing surface tension of thesolvents, that is, the unbinding force is proportional to
the surface tension of the solvent. Since surface tension is defined as the force acting on a hypotheticalline of unit length arbitrarily drawn on the liquid surface, the obtained linear relationship indicates that
there exists a specific ‘‘effective length’’ that produces
the observed unbinding force; surface tension unbinding force-vdW force=effective length. Fromthe gradient of the linear relationship shown in Fig. 3(a),the effective length is estimated to be 1:07  0:13 nm,
which is consistent with the perimeter of the adamantane
molecule, 1:3 nm. This is the first direct evidence showing that surface tension works in the host-guest system atthe single-molecule level.
From the linear relationship shown in Fig. 3(a), theintrinsic vdW force can be determined by extrapolating
the linear relationship to zero surface tension, and the valueis 18  7 pN; this makes the comparison with the theoretical analysis possible, for example, using the structure
determined by the x-ray diffraction method. By subtracting
the vdW force from the measured force, the force causedby the surface tension for each liquid can be evaluated.
This is also the first time that the factors contributing to thehost-guest interaction in a liquid environment are discriminated at the single-molecule level. According to themacroscopic analysis, the vdW force component is about

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70% of the total force [29], while it is 25% (100% water)—
50% (100% methanol) in this case, as shown in Fig. 3(a).
This can be attributed to the fact that the vdW force
measured here is just on the unbinding process of thecomplex structure, where vdW force is weaker than thatfor the stable conformation (Fig. 4).
The linear relationship in Fig. 3(a) indicates that thesurface tension determined by AFM measurement, thatis, unbinding force minus vdW force divided by the effective length, has the same function of the mix ratios of themethanol-water solutions as the macroscopic relationshipshown in Fig. 1(d). To further elucidate the relationship ofthe nanoscale mechanism with the macroscopic mechanism, the unbinding force obtained using AFM measurement is plotted as a function of the mix ratios of themethanol-water solutions in Fig. 3(b). Here, it is clearlyshown that the characteristic of the solvophobic effectobtained on the nanoscale, namely, the unbinding force
minus vdW (18  7 pN) divided by the effective length(1:07  0:13 nm), is in good agreement with that of themacroscopic surface tension of the solution shown in
Fig. 1(d).
As mentioned earlier, the surface tension of water islarger than that expected from the linear relationshipfrom the mix ratio of the methanol-water solutions, indicating that the interaction between water molecules isstronger than those between molecules of other solvents,
which is considered to be induced by the strong hydrogenbond network [30]. Our result is the first demonstration thatshows the existence of a specific network of water molecules in the host-guest system, which provides us with thebasis of the results of the macroscopic analysis.
In conclusion, the effectiveness of the mechanism of
surface tension on the host-guest system was demonstrated
at the single-molecule level by measuring the unbinding
force in a liquid environment. The contribution of surface
tension was quantitatively distinguished from the intrinsic
vdW. The effective length that produces the detected force
through the mechanism of surface tension was determined
to be 1:07  0:13 nm, which is consistent with the perimeter of the adamantane molecule, 1:3 nm. Specific strong

(b)

0

0

Unbinding force (pN)
20 40 60 80 100

UF - vdW(pN/nm)Effective length
60 40 200080

Unbinding force (pN)
20 40 60 80 100

(a)

60
80
20
40
Surface tension (mN/m)

020 40 60 80 100% Water (v/v)

FIG. 3. Obtained unbinding forces as a function of surface
tension of solvents (a) and as a function of the mix ratios ofthe methanol-water solutions (b). Right side axis represents thesurface tensions determined using AFM measurement, i.e., unbinding force (UF) minus vdW force divided by effective length.

FIG. 4 (color). Schematic illustrations showing the differencein vdW forces appearing in stable and unbinding-process conformations.

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PHYSICAL REVIEW LETTERS

interaction of water molecules was also confirmed on thenanoscale.
This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan. Oneof the authors (S. Y.) was financially supported by theJapan Society for the Promotion of Science (JSPS). We
thank Ms. Rie Yamashita for her help in preparing thisLetter.

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[21] The oxygen atom of the ether bond between the adamantane molecule and the decyl-thiol molecule could form ahydrogen bond with the 14 hydoxyl groups present at the
periphery of the CyD cage. However, since adamantane
has a bulky structure and the free space around the oxygen
atom of the ether is small, it is not easy to form its
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CyD. Water molecules are small and can come close to
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