A look inside the cavity of hydrated a-cyclodextrin: A computer simulation study Herbert C. Georg, Kaline Coutinho * , Sylvio Canuto Instituto de Fı ´sica, Universidade de Sa ˜o Paulo, CP 66318, 05315-970 Sa ˜o Paulo, SP, Brazil Received 15 November 2004; in final form 4 June 2005 Available online 8 August 2005 Abstract Monte Carlo simulations of hydrated a-cyclodextrin are made to analyze the properties of the water molecules inside the hydro- phobic cavity. An average of five water molecules is found in the cavity, where only 2.4 are hydrogen bonded to the a-CD. The hydrogen-bond interactions between the a-CD and the inner water molecules are reduced when compared with those outside the cavity. The free energy of binding one water molecule inside the hydrated a-CD is obtained using the thermodynamic perturbation theory. From these the entropy contribution is obtained to ascertain the hydrophobic strength of the cavity. Ó 2005 Elsevier B.V. All rights reserved. 1. Introduction Considerable interest is devoted to the chemistry and technology of cyclodextrins (CD) [1,2]. CDs are starch- derived molecules possessing a hydrophobic cavity with an enormous host potential that make them very impor- tant for molecular encapsulation and for drug carriers [3]. Different cavity sizes are possible depending on the number of elementary glucose units. In spite of the great number of investigations made on CDs, the knowledge of the cavity properties is still limited. In this direction, it is useful to obtain additional information that could be helpful in understanding the hydrophobic activity of their cavities and the driving forces for the inclusion mechanism. There are several studies concerned with the properties of CDs in water [4–13]. Experimental information has been obtained in the crystalline form [4–7] but that does not emphasize the role of liquid water, although it provides information regarding the hydration and possible number of surrounding water molecules. This subject has been pursued intensely by Saenger et al. [14]. Early computer simulations have compared different CDs and stressed the effects of the solvent on their properties [8]. There are many previous theoretical studies of CDs, both isolated and in water, as described in a review article [9]. A recent theoretical study [10], at the semi-empirical level, analyzed the for- mation of the observed crystalline hexahydrate that in- cludes two water molecules inside the cavity [4,11]. Recent spectroscopic studies [15,16] have probed the influence of the hydrophobic cavity in the orientation of the encapsulated guest molecule. In this Letter, we study the cavity of the six-glucose a- CD (Fig. 1) in water at room temperature. We use Monte Carlo computer simulation to analyze the behav- ior of the water molecules inside the hydrophobic cavity of a-CD. We determine the average number of water molecules and their interaction strength. We analyze the effect of the confinement on the water molecules inside the cavity comparing the simulation of hydrated a-CD with another simulation where the atoms of the a-CD are considered as simple hard spheres. In addi- tion, we obtain the Gibbs free energy of binding a water molecule inside the cavity of a-CD using the thermody- namic perturbation theory [17,18]. Using the calculated values of the free energy and the enthalpy of binding, we estimate the entropy contribution to stabilize the process 0009-2614/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2005.07.036 * Corresponding author. Fax: +55 11 3091 6831. E-mail address: kaline@if.usp.br (K. Coutinho). www.elsevier.com/locate/cplett Chemical Physics Letters 413 (2005) 16–21