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Apr 7, 2016 - ABSTRACT: Herein, we present an endeavor toward exploring the lacuna underlying the host:guest chemistry of inclusion complex formation ...
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Interaction of Bile Salts with β‑Cyclodextrins Reveals Nonclassical Hydrophobic Effect and Enthalpy−Entropy Compensation Bijan K. Paul, Narayani Ghosh, and Saptarshi Mukherjee* Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal Bypass Road, Bhopal 426066, Madhya Pradesh, India S Supporting Information *

ABSTRACT: Herein, we present an endeavor toward exploring the lacuna underlying the host:guest chemistry of inclusion complex formation between bile salt(s) and β-cyclodextrin(s) (βCDs). An extensive thermodynamic investigation based on isothermal titration calorimetry (ITC) demonstrates a dominant contribution from exothermic enthalpy change (ΔH < 0) accompanying the phenomenon of inclusion complex formation, along with a relatively smaller contribution to total free energy change from the entropic component. However, the negative heat capacity change (ΔCp < 0) displays the hallmark for a pivotal role of hydrophobic effect underlying the interaction. Contrary to the classical hydrophobic effect, such apparently paradoxical thermodynamic signature has been adequately described under the notion of “nonclassical hydrophobic effect”. On the basis of our results, the displacement of disordered water from hydrophobic binding sites has been argued to mark the enthalpic signature and the key role of such interaction forces is further corroborated from enthalpy−entropy compensation behavior showing indication for almost complete compensation. To this end, we have quantified the interaction of two bile salt molecules (namely, sodium deoxycholate and sodium glycocholate) with a series of varying chemical substituents on the host counterpart, namely, βCD, (2-hydroxypropyl)-βCD, and methyl βCD. mouse major urinary protein (rMUP).14 Such an enthalpydriven hydrophobic interaction has furnished the concept of the nonclassical hydrophobic effect.8,13−21 Though a tenable rationale bridging the thermodynamic origin of the classical and nonclassical hydrophobic effects is still far from being completely understood, the fact that the nonclassical effect is characterized by a thermodynamic hallmark of a negative change in heat capacity (ΔCp < 0), which is rather typical of its classical counterpart,8,10,13−21 points toward solvent reorganization as to be the molecular basis of both. Furthermore, the origin of the hydrophobic effect may also vary depending on the concerned partners undergoing a specific interaction.8,10,13−21 Thus, a complete understanding of the thermodynamic basis of the hydrophobic effect remains too inherently complex to be encompassed within one or two models taking into account a few key events that predominate a given hydrophobic association. This is further intensified by the difficulty of a relative lack of suitable experimental techniques capable of detecting the molecular changes following a hydrophobic interaction, particularly the modulation in the dynamics of the water of hydration.10,13 Isothermal titration calorimetry (ITC) is an excellent experimental technique to

1. INTRODUCTION The notion of formation of structured (or ordered) water surrounding nonpolar groups has been conventionally invoked to lay the foundation of the “classical hydrophobic effect”1−8 which accompanies enhancement of apparent heat capacity of the solute in aqueous medium.2 Drawing on this, the structured water molecules are believed to be characterized by a higher heat capacity and lower entropy compared to bulk water which in turn leads to a classical interpretation of the hydrophobic effect in terms of favorable entropy change (TΔS > 0) together with a negative change in constant pressure heat capacity (ΔCp < 0).1,4−10 Consequently, the genesis of the concept of “hydrophobic hydration” finds its link to such an interpretation of the entropy-driven hydrophobic effect. The process of hydrophobic hydration is characterized by a large drop of entropy accompanying aggregation of hydrophobic solutes (shielding of nonpolar surfaces from the water surface).8,11−13 The loss of entropy arises from the solvent-excluded volume effect underlying the formation of a cavity to accommodate the hydrophobic groups.8,11−13 However, the nature of structuring of the ordered water molecules in the context of classical hydrophobic effect and hence a complete molecular level interpretation of the same still eludes our understanding. Of late, the enthalpy-driven thermodynamic signature of the hydrophobic effect has also been identified, for example, in the interaction of hydrophobic ligand(s) with recombinant © XXXX American Chemical Society

Received: February 9, 2016 Revised: March 15, 2016

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DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B

In this context, it is pertinent to note that the sign convention of our instrument (Nano ITC, TA Instrument) describes an exothermic (or endothermic) process through upward (or downward) calorimetric traces.22−24 It is important to state that the upward/downward trend of the raw ITC data is not universal, rather the sign of ΔH obtained from deconvolution of the experimental data reflect the genuine thermodynamic signature and we have interpreted our data accordingly.

determine the thermodynamic and association parameters (including association constant (Ka) and stoichiometry (n)) of a given interaction simultaneously in a single experiment at a given temperature.6,8,10,13,15,18−21 Herein, the key focus of the work involves an extensive ITC-based thermodynamic characterization of the host:guest inclusion complex formation reaction between bile salt(s) and β-cyclodextrin(s) (βCDs). To this effect, the inclusion complex formation of two bile salt molecules, sodium deoxycholate (NaDC) and sodium glycocholate (NaGC), with βCD has been undertaken. In addition, our endeavor extends to yield generalized results in this context by involving three different chemical variants of βCD, namely, βCD, (2-hydroxypropyl)-β-cyclodextrin (HPβCD), and methyl-β-cyclodextrin (MeβCD). Very recently, we have reported the governing role played by the nonclassical hydrophobic effect in NaDC:βCD interaction.22 However, the present results encompass a broader spectrum of the interaction scenario and establish the mechanistic nature of the force of interaction underlying the phenomena of inclusion complex formation between bile salt(s) and βCDs in a more generalized context. A meticulous estimation of the association and thermodynamic parameters of the bile salt(s):βCD(s) inclusion complex formation reaction reveals that the process is characterized by an exothermic enthalpy change (ΔH < 0) essentially constituting the total free energy change (ΔG). The negative change of heat capacity (ΔCp < 0) accompanying the processes unveils the instrumental role of hydrophobic forces. The apparently paradoxical thermodynamic signature of the interaction process has been adequately described by the nonclassical hydrophobic effect. Experimental evidence for enthalpy−entropy compensation behavior further corroborates the pivotal role of hydrophobic effect governing the phenomena of inclusion complex formation.

3. RESULTS AND DISCUSSION 3.1. Thermodynamics of Bile Salt:βCD Inclusion Complex Formation: The Nonclassical Hydrophobic Effect. The typical ITC heat burst curves for titration of NaDC and NaGC with HPβCD are displayed in Figure 1 and

Figure 1. Rep resentative ITC profile for the titration of (a) NaDC with HPβCD and (b) NaGC with HPβCD. The top panels display the integrated heat burst curves at 298 K (appropriately corrected for heat of dilution). The bottom panels present the ITC enthalpograms extracted at various temperatures (288 K (□); 298 K (−▲−); 308 K (−■−); 318 K (−●−); 333 K (−○−)). The solid lines are the best fit lines to the experimental data according to a one set of sites binding model. The power sign convention for the heat burst curves in ITC measurement: exothermic (or endothermic) process represented by upward (or downward) calorimetric traces (see also Experimental Section).

2. EXPERIMENTAL SECTION 2.1. Materials. Sodium deoxycholate (NaDC), sodium glycocholate (NaGC), βCD, HPβCD, and MeβCD were purchased from Sigma-Aldrich Chemical Co., USA, and used as received. Phosphate buffer was obtained from Sigma-Aldrich Chemical Co., USA, and 10 mM phosphate buffer of pH 7.40 was prepared in triply distilled deionized Millipore water. 2.2. Instrumentation. The isothermal titration calorimetry (ITC) experiments for characterizing the thermodynamics of bile salt(s):βCD(s) interaction were performed on a Nano ITC, TA Instrument. A total of 25 aliquots of βCD (or HPβCD or MeβCD) solution in aqueous buffer of pH 7.40 was injected in 2 μL intervals from a syringe rotating at 300 rpm into the sample chamber containing the bile salt (NaDC or NaGC) solution in aqueous buffer of pH 7.40 maintaining an interval of 120 s between successive injections. Prior to loading in the ITC sample chamber particular care was taken for thorough degassing of all the solutions (bile salt or βCD) in order to avoid bubble formation during titration. The heat of dilution was evaluated within an identical experimental window in a control experiment by titration of βCD solution into neat aqueous buffer. The heat burst curves conforming to a given interaction were then determined following the appropriate correction of heat of dilution, and the resulting data were analyzed on NanoAnalyze software (version 2.4.1) according to a model for one set of binding sites.22−24 The reported experimental parameters are an average of four individual measurements.

the relevant thermodynamic parameters are compiled in Table 1 (interaction of NaDC with HPβCD and MeβCD) and Table 2 (interaction of NaGC with three different βCDs) (the ITC results for interaction of NaDC and NaGC with MeβCD and βCD are presented in Figure S1 and S2 of of the Supporting Information (SI). The power sign convention for the heat burst curves in ITC measurement is as follows: exothermic (or endothermic) process represented by upward (or downward) calorimetric traces (see also Experimental Section)).22−24 Despite several attempts in the literature6,25−30 regarding the host:guest interaction involving cyclodextrins, an in-depth understanding of the interaction scenario of bile salts with cyclodextrins still offers considerable ambiguity and hence ample scope for exploration. However, a precise description of the enthalpic and entropic components comprising the overall interaction may be enormously complex because of contributions from a vista of interactions involving modulations in the degrees of freedom of the interacting species, solvent rearrangements, and so forth. Nevertheless, our efforts extend to the determination of the thermodynamics of the interaction over a range of temperatures which can in turn provide valuable insights into the molecular level interpretation of the interaction.8,14−16,19,20,28 The host:guest interaction of both the bile salts (NaDC and NaGC) with all three host systems (βCD, HPβCD, and MeβCD) is found to follow a 1:1 stoichiometry (Tables 1 and B

DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B Table 1. Thermodynamic Parameters for Interaction of the NaDC with HPβCD, MeβCDa T (K)

a

Ka × 10−3 (M−1)

ΔH (kJ mol−1)

n

288 298 308 318 333

3.21 2.45 2.24 1.83 1.75

± ± ± ± ±

0.13 0.1 0.09 0.07 0.07

1.1 0.95 0.88 0.92 0.94

± ± ± ± ±

0.1 0.1 0.1 0.1 0.1

293 298 308 318 333

4.10 3.77 3.86 2.79 2.07

± ± ± ± ±

0.16 0.15 0.15 0.11 0.22

0.89 0.94 0.93 0.96 0.94

± ± ± ± ±

0.1 0.1 0.1 0.1 0.1

TΔS (kJ mol−1)

Interaction of NaDC with HPβCD −2.97 ± 0.12 16.37 ± 0.7 −7.66 ± 0.31 11.72 ± 0.5 −12.2 ± 0.5 7.56 ± 0.3 −17.0 ± 0.7 2.86 ± 0.12 −20.29 ± 0.8 0.40 ± 0.2 Interaction of NaDC with MeβCD −5.92 ± 0.24 14.35 ± 0.57 −7.67 ± 0.31 12.73 ± 0.51 −10.37 ± 0.41 10.78 ± 0.43 −12.96 ± 0.52 8.02 ± 0.32 −15.9 ± 0.64 5.25 ± 0.21

ΔG (kJ mol−1)

ΔCp (J mol−1 K−1)

−19.33 −19.38 −19.76 −19.86 −20.69

± ± ± ± ±

0.8 0.8 0.8 0.8 0.82

−394.37

−20.27 −20.40 −21.15 −20.98 −21.15

± ± ± ± ±

0.81 0.82 0.84 0.84 0.85

−248.5

The error bars are deduced from four individual measurements. The results of NaDC:βCD interaction are reported elsewhere (ref 22).

Table 2. Thermodynamic Parameters for Interaction of the NaGC with HPβCD, MeβCD and βCDa T (K)

a

Ka × 10−3 (M−1)

ΔH (kJ mol−1)

n

288 293 298 308 318 333

2.47 2.41 2.35 2.13 1.80 1.35

± ± ± ± ± ±

0.1 0.1 0.09 0.08 0.07 0.05

0.89 0.89 0.89 0.87 0.82 0.85

± ± ± ± ± ±

0.1 0.1 0.1 0.1 0.1 0.1

288 298 308 318 333

4.10 3.17 2.92 2.19 1.71

± ± ± ± ±

0.16 0.13 0.11 0.10 0.07

0.79 0.80 0.78 0.90 0.88

± ± ± ± ±

0.1 0.1 0.1 0.1 0.1

298 308 318 333

3.77 3.06 2.26 1.46

± ± ± ±

0.15 0.12 0.09 0.06

0.74 0.80 0.89 0.99

± ± ± ±

0.1 0.1 0.1 0.1

TΔS (kJ mol−1)

Interaction of NaGC with HPβCD −2.26 ± 0.09 16.55 ± −3.51 ± 0.14 15.68 ± −4.75 ± 0.19 14.48 ± −7.46 ± 0.3 12.17 ± −9.90 ± 0.4 9.60 ± −12.05 ± 0.5 7.82 ± Interaction of NaGC with MeβCD −4.98 ± 0.2 15.13 ± −7.76 ± 0.31 12.81 ± −10.51 ± 0.4 9.93 ± −12.37 ± 0.49 7.96 ± −13.87 ± 0.6 6.63 ± Interaction of NaGC with βCD −16.57 ± 0.66 3.84 ± −17.24 ± 0.69 3.32 ± −17.72 ± 0.7 2.65 ± −18.2 ± 0.73 1.98 ±

ΔG (kJ mol−1)

ΔCp (J mol−1 K−1)

0.66 0.63 0.6 0.5 0.4 0.31

−18.81 −19.18 −19.23 −19.63 −19.51 −19.87

± ± ± ± ± ±

0.75 0.77 0.76 0.78 0.78 0.79

−224.27

0.60 0.5 0.4 0.32 0.2

−20.11 −20.57 −20.44 −20.33 −20.5

± ± ± ± ±

0.8 0.8 0.81 0.81 0.8

−199.8

0.15 0.13 0.11 0.08

−20.41 −20.56 −20.37 −20.18

± ± ± ±

0.81 0.82 0.81 0.8

−45.89

The error bars are deduced from four individual measurements.

2).22 The dehydration of the apolar (hydrophobic) surfaces following encapsulation of bile salt molecules within the hydrophobic cavity of βCDs is argued to promote the formation of the inclusion complex,6,8,14−16,19,20,22,24−30 which apparently appears to conform to the classical hydrophobic effect (release of structured water, that is, water of hydrophobic hydration)1−8 which is conventionally characterized by a favorable entropic (TΔS > 0) and an unfavorable enthalpic (ΔH > 0) contribution. However, the thermodynamics of the presently investigated interaction phenomena is found to display a seemingly paradoxical situation in which the overall process is predominantly enthalpy-driven with small entropic contribution to the total free energy change (ΔG), Tables 1 and 2. The process of bile salt:βCD inclusion complex formation is found to be designated by exothermic enthalpy change (ΔH < 0) and the absolute magnitude of ΔH gradually increases with temperature (though it remains negative), Tables 1 and 2. The dependence of ΔH on temperature is exploited to estimate the constant pressure heat capacity change (ΔCp) accompanying the process according to the standard thermodynamic relationship:8,10 ΔCp = δ(ΔH )/δT

A negative change of heat capacity (ΔCp < 0, Tables 1 and 2) dictates the thermodynamic signpost for hydrophobic interaction6,8,14−16,19,20,22,24−28 (ΔCp (in J mol−1 K−1) values are −394.37 for NaDC:HPβCD, −248.5 for NaDC:MeβCD,22 −122.35 for NaDC:βCD, and −224.27 for NaGC:HPβCD, −199.8 for NaGC:MeβCD, −45.89 for NaGC:βCD). The results are presented in Figure 2. From the viewpoint of the classical hydrophobic effect a negative change in heat capacity (ΔCp < 0) essentially correlates with the release of structured water molecules as a result of inclusion complex formation (in which the apolar (hydrophobic) surfaces are shielded from bulk water). The ordered water molecules, that is, the water in the hydration shells of hydrophobic moieties are believed to have characteristic higher heat capacity and lower entropy compared to that of bulk water which follows that the formation of inclusion complex accompanies a reduction of the hydration shell accounting for the negative ΔCp coupled with a favorable entropy change (TΔS > 0).1,4−10 However, the present findings are apparently contradictory to this view (Tables 1 and 2), displaying a small contribution from the entropic component which emanates from the release of solvent water molecules, rather the thermodynamic parameters of the studied

(1) C

DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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methyl and hydroxypropyl substituents might play a role in governing the complexation thermodynamics of cyclodextrins (MeβCD and HPβCD): (i) the hydroxypropyl moiety, unlike the methyl substituent, may interact with water molecules in near vicinity in addition to participation in intramolecular hydrogen bond formation,1,25,28,36−38 (ii) by virtue of its larger surface area, the hydroxypropyl substituent may cause greater degree of dehydration of the hydrophobic guest molecules compared to the methyl substituent.1,25,28,36−38 Thus, the relative magnitudes of the thermodynamic parameters (ΔH and ΔS) for inclusion complex formation of cyclodextrins with the bile salts will be governed by a complex interplay of various individual forces.1,25,28,36−38 However, the aforesaid arguments would imply a greater extent of reduction of the hydration shell involving the interacting species (βCDs and bile salt molecules) following inclusion complex formation in HPβCD compared to MeβCD and hence justifying the magnitude of ΔCp following the order HPβCD > MeβCD > βCD during interaction with both NaDC and NaGC (Tables 1 and 2). 3.2. Enthalpy−Entropy Compensation. A deeper perusal of the thermodynamic parameters characterizing the bile salt:βCD inclusion complex formation reveals another salient feature of the interaction process, that is, “enthalpy−entropy compensation (EEC)”. The total free energy change (ΔG) of the process is found to remain reasonably invariant with temperature as a consequence of mutually compensating variation of the enthalpic (ΔH) and entropic (TΔS) contributions with temperature (Tables 1 and 2). These results are depicted in Figure 3a (for NaDC:HPβCD interaction) and

Figure 2. Variation of enthalpy changes (ΔH in kJ mol−1) with temperature for (a) interaction of NaDC with HPβCD (−○−) and MeβCD (−●−), and (b) interaction of NaGC with HPβCD (−○−), MeβCD (−●−), and βCD (−■−). The error bars are within the marker symbols if not visible. The results of NaDC:βCD interaction are reported elsewhere (ref 22).

interactions unveil the signature of an enthalpy-driven process. In parity with a body of investigations reported in the literature,8,14,24−28,31,32 the present results highlight the subtle imbalance between solute−solvent and solute−solute dispersion interactions that are prevalent before and after the association processes.8 At this stage, it can be argued that formation of the bile salt:βCD inclusion complex follows expulsion of disordered water molecules from the hydrophobic (apolar) binding pockets of the interacting partners which accompanies only a minor entropic contribution given that such water molecules are already possessing a significant degrees of freedom.18,33−35 On the contrary, a predominant enthalpic contribution (ΔH < 0) can be expected following the displacement of these water molecules as this would markedly enhance the probability of formation of new hydrogen bonds of these water molecules with bulk water molecules. It is wellknown that water in the proximity of hydrophobic (apolar) surfaces involves fewer hydrogen bonds compared those in the bulk.18,33−35 Thus, the argument of displacement of disordered water molecules from the hydrophobic surface(s) can be invoked to rationalize a dominant component from favorable enthalpy change (ΔH < 0) contributing to the total free energy change (ΔG) of the interaction process compared to entropic contribution. Similar examples of favorable enthalpic contribution governing a hydrophobic interaction have also been reported in the literature for a variety of interaction phenomena.8,14,22,24−28,31,32 Cumulatively, these observations thus point out an enthalpydriven hydrophobic interaction underlying the phenomenon of bile salt:βCD inclusion complex formation, on contrary to the entropy-driven classical hydrophobic effect. Consequently, this has been rationalized on the basis of ‘nonclassical hydrophobic effect’.6,8,14−16,19,20,22,24−28,31−35 In aqueous solution, the hydrophobic cyclodextrin cavity is occupied by water molecules which are energetically unfavorable.25,36 In general, the formation of inclusion complex of cyclodextrins with appropriate guest molecules can be governed by a plethora of interaction forces. However, the factors that significantly contribute to the thermodynamics of inclusion complex formation differing from the classical hydrophobic effect include displacement of the water molecules from the cyclodextrin cavity to the bulk,36,37 dehydration of the hydrophobic guest, and conformational modulation of the cyclodextrin moiety.1,36−38 Thus, the contribution from many individual interactions leads to an inherently complicated interpretation of the thermodynamic parameters underlying the process.1,25,28,36−38 However, the structural differences between

Figure 3. Variation of relevant thermodynamic parameters as a function of temperature (ΔH in kJ mol−1 (−○−); TΔS in kJ mol−1 (−●−); ΔG in kJ mol−1 (−■−)) for (a) NaDC:HPβCD and (b) NaGC:HPβCD interactions. The error bars are within the marker symbols if not visible.

Figure 3b (for NaGC:HPβCD interaction). The results of the interaction of NaDC/NaGC with βCD and MeβCD are produced in Figures S3 and S4 of Supporting Information. Usually, such EEC behavior is believed to reflect a typical signature of hydrophobic contribution to the binding energies and hence corroborates the occurrence of solvent reorganization (that is, significant modulation of the hydration structure) as a result of the interaction.8,39−42 In this context it is important to note that the observed EEC behavior conforms to a linear relationship having slope close to unity for the variation of the enthalpic (ΔH) versus entropic (TΔS) components (representative results for interaction of NaDC and NaGC with HPβCD are illustrated in Figure 4, the results for interaction of NaDC/NaGC with βCD and MeβCD are given in Figures S5 and S6 of Supporting Information). This implies the occurrence of an almost complete compensation behavior which is usually ensured under the thermodynamic conditions: ΔCp ≠ 0 and ΔS < ΔCp.10,39−42 D

DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS B.K.P. acknowledges postdoctoral research fellowship from IISER Bhopal, and N.G. acknowledges CSIR, India, for a research fellowship.

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Figure 4. Linear dependence of variation of ΔH with TΔS for (a) NaDC:HPβCD (−○−; slope = 1.07) and (b) NaGC:HPβCD (−●−; slope = 1.09) interactions. The error bars are within the symbol if not visible.

(1) Tanford, C. The Hydrophobic Effect: Formation of Micelles and Biological Membranes; Wiley: NewYork, 1980. (2) Edsall, J. T. Apparent Molal Heat Capacities of Amino Acids and Other Organic Compounds. J. Am. Chem. Soc. 1935, 57, 1506−1507. (3) Frank, H. S.; Evans, M. W. Free Volume and Entropy in Condensed Systems III. Entropy in Binary Liquid Mixtures; Partial Molal Entropy in Dilute Solutions; Structure and Thermodynamics in Aqueous Electrolytes. J. Chem. Phys. 1945, 13, 507−532. (4) Kauzmann, W. Some Factors in the Interpretation of Protein Denaturation. Adv. Protein Chem. 1959, 14, 1−63. (5) Sturtevant, J. M. Heat Capacity and Entropy Changes in Processes Involving Proteins. Proc. Natl. Acad. Sci. U. S. A. 1977, 74, 2236−2240. (6) Ollila, F.; Pentikäinen, O. T.; Forss, S.; Johnson, M. S.; Slotte, J. P. Characterization of Bile Salt/Cyclodextrin Interactions Using Isothermal Titration Calorimetry. Langmuir 2001, 17, 7107−7111. (7) Yaminsky, V.; Ohnishi, S. Physics of Hydrophobic Cavities. Langmuir 2003, 19, 1970−1976. (8) Syme, N. R.; Dennis, C.; Phillips, S. E. V.; Homans, S. W. Origin of Heat Capacity Changes in a “Nonclassical” Hydrophobic Interaction. ChemBioChem 2007, 8, 1509−1511. (9) Baldwin, R. L. Temperature Dependence of the Hydrophobic Interaction in Protein Folding. Proc. Natl. Acad. Sci. U. S. A. 1986, 83, 8069−8072. (10) Paul, B. K.; Ghosh, N.; Mukherjee, S. Interplay of Multiple Interaction Forces: Binding of Norfloxacin to Human Serum Albumin. J. Phys. Chem. B 2015, 119, 13093−13102. (11) Graziano, G. Hydration Entropy of Polar, Nonpolar and Charged Species. Chem. Phys. Lett. 2009, 479, 56−59. (12) Graziano, G. Scaled Particle Theory Study of the Length Scale Dependence of Cavity Thermodynamics in Different Liquids. J. Phys. Chem. B 2006, 110, 1142−1426. (13) Nasief, N. N.; Hangauer, D. Influence of Neighboring Groups on the Thermodynamics of Hydrophobic Binding: An Added Complex Facet to the Hydrophobic Effect. J. Med. Chem. 2014, 57, 2315−2333. (14) Rick, S. W. Heat Capacity Change of the Hydrophobic Interaction. J. Phys. Chem. B 2003, 107, 9853−9857. (15) Seelig, J.; Ganz, P. Nonclassical Hydrophobic Effect in Membrane Binding Equilibria? Biochemistry 1991, 30, 9354−9359. (16) Meyer, E. A.; Castellano, R. K.; Diederich, F. Interactions with Aromatic Rings in Chemical and Biological Recognition. Angew. Chem. 2003, 115, 1244−1287. (17) Lemieux, R. U. How Water Provides the Impetus for Molecular Recognition in Aqueous Solution. Acc. Chem. Res. 1996, 29, 373−380. (18) Mecinovic, J.; Snyder, P. W.; Mirica, K. A.; Bai, S.; Mack, E. T.; Kwant, R. L.; Moustakas, D. T.; Heroux, A.; Whitesides, G. M. Fluoroalkyl and Alkyl Chains Have Similar Hydrophobicities in Binding to the “Hydrophobic Wall” of Carbonic Anhydrase. J. Am. Chem. Soc. 2011, 133, 14017−14026. (19) Garidel, P.; Hildebrand, A.; Neubert, R.; Blume, A. Thermodynamic Characterization of Bile Salt Aggregation as a Function of Temperature and Ionic Strength Using Isothermal Titration Calorimetry. Langmuir 2000, 16, 5267−5275. (20) Domingues, T. M.; Mattei, B.; Seelig, J.; Perez, K. R.; Miranda, A.; Riske, K. A. Interaction of the Antimicrobial Peptide Gomesin with Model Membranes: A Calorimetric Study. Langmuir 2013, 29, 8609− 8618.

Recently, the thermodynamic origin of enthalpy−entropy compensation has been rationalized on the basis of the Carnot cycle concept which has been employed to lead an interpretation based on interplay of entwined motions of the interacting species which involves the solvent molecules as well, in addition to the ligand(s) and the macromolecule(s)).43

4. CONCLUSIONS Herein, we have performed an extensive analysis of the thermodynamics of host:guest inclusion complex formation reaction between bile salts (NaDC and NaGC) and βCD having various chemical substituents (HPβCD, MeβCD, and βCD). Our results unveil a significantly exothermic (ΔH < 0) contribution to the total free energy change (ΔG) of the process of host:guest complex formation as compared to a relatively smaller entropic component. However, the instrumental contribution of the hydrophobic effect underlying the phenomena of inclusion complex formation is demonstrated by the negative change in heat capacity (ΔCp < 0). The expulsion of disordered water molecules from the hydrophobic binding pockets has been invoked to assist the observation of dominant enthalpic (exothermic, ΔH < 0) contribution in this hydrophobic binding phenomenon. Cumulatively, these results pose an apparently paradoxical thermodynamic signature in characterizing the interaction(s) which can be comprehensively rationalized in terms of the nonclassical hydrophobic effect. Another intriguing feature of the interaction is identified in the context of significant enthalpy−entropy compensation phenomenon making the free energy of interaction nearly independent of temperature. This signifies a predominant hydrophobic component in the overall interaction energy.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b01385. ITC titration data for NaDC with MeβCD and NaGC with MeβCD and βCD, variation of relevant thermodynamic parameters as a function of temperature for NaDC:MeβCD, NaGC:MeβCD, and NaGC:βCD interactions, ΔH versus TΔS plots for NaDC:βCD, NaGC:MeβCD, and NaGC:βCD interactions (PDF)

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Corresponding Author

*E-mail: [email protected]. E

DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.jpcb.6b01385 J. Phys. Chem. B XXXX, XXX, XXX−XXX