Combined crystallographic and solution molecular dynamics study of allosteric effects in ester and ketone p-tert-butylcalix[4]arene derivatives and their complexes with acetonitrile, Cd(II), and Pb(II).

We describe here a procedure to bridge the gap in the field of calixarene physicochemistry between solid-state atomic-resolution structural information and the liquid-state low-resolution thermodynamics and spectroscopic data. We use MD simulations to study the kinetics and energetics involved in the complexation of lower rim calix[4]arene derivatives (L), containing bidentate ester (1) and ketone (2) pendant groups, with acetonitrile molecule (MeCN) and Cd(2+) and Pb(2+) ions (M(2+)) in acetonitrile solution. On one hand, we found that the prior inclusion of MeCN into the calix to form a L(MeCN) adduct has only a weak effect in preorganizing the hydrophilic cavity toward metal ion binding. On the other hand, the strong ion-hydrophilic cavity interaction produces a wide open calix which enhances the binding of one MeCN molecule (allosteric effect) to stabilize the whole (M(2+)) L(MeCN) bifunctional complex. We reach two major conclusions: (i) the MD results for the (M(2+)) 1(MeCN) binding are in close agreement with the "endo", fully encapsulated, metal complex found by X-ray diffraction and in vacuo MD calculations, and (ii) the MD structure for the more flexible 2 ligand, however, differs from the also endo solid-state molecule. In fact, it shows strong solvation effects at the calixarene lower bore by competing MeCN molecules that share the metal coordination sphere with the four CO oxygens of an "exo" (M(2+)) 2(MeCN) complex.