Molecular mechanics calculations of molecular and chiral recognition by cyclodextrins.: Is it reliable?: The selective complexation of decalins by β-cyclodextrin

Molecular mechanics calculations are frequently used to rationalize experimental findings concerning molecular and chiral recognition by cyclodextrins although the reliability of the method in general and the influence of choice of the parameters in particular has not almost been analyzed. In this work molecular and chiral recognition of decalin isomers by beta-cyclodextrin was studied using AMBER, CVFF, CFF9I, and MMX force fields and five values of dielectric constant epsilon = 1, 2, 4, 10, 20. Most calculations yielded consistently lower stability of the complex with trans-decalin. However, in most cases the absolute value of the energy difference between the stabilization energies of the complexes with the latter isomer and the one with cis-decalin closer to it, \Delta Delta E-molec\ characterizing molecular recognition was found smaller than the corresponding value involving cis-decalin enantiomers, \Delta Delta E-chir\ = \Delta EM-cis - Delta EP-cis\ characterizing chiral recognition. The calculations indicate no preference for complexation with tither hl-cis or P-cis decalin enantiomer. Therefore, we believe that MM is not suitable for reliable analysis of chiral recognition by cyclodextrins. Although the epsilon value of 1 was found unreliable for molecular mechanics calculations using all FF under study, our preliminary results of molecular dynamics calculations in water for the complexes of camphor and pinene enantiomers with alpha-cyclodextrin using the latter value yielded qualitatively correct results. (C) 2000 Elsevier Science B.V. All rights reserved.