van der Waals host-guest complexes: Can one predict complexation selectivity of neutral guests by a cryptophane? MD-FEP studies in gas phase and chloroform solution
✍ Scribed by Varnek, Alexandre; Helissen, Severine; Wipff, Georges; Collet, Andr�
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 336 KB
- Volume
- 19
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
Quantitative assessment of the ''best fit'' between neutral molecules and the cavity of a ''rigid'' neutral receptor is a challenging task in supramolecular chemistry, drug design, and biology. We investigate this question by molecular dynamics and free-energy perturbation simulations . Ž . performed on the macrocyclic ligand cryptophane-E L and its L S complexes Ž . with three tetrahedral guests S s CH Cl , CHCl , and CCl in the gas phase 2 2 3 4 and in chloroform solution. The van der Waals interactions are shown to play a crucial role in the calculated complexation selectivity. Calculations using Lennard᎐Jones 6-12 potentials and ''standard'' OPLS R U and parameters Cl Cl for the Cl atoms of S lead to a preference for CCl , in contrast to the selectivities 4 Ž . observed experimentally in solution CHCl ) CH Cl ) CCl . Based on 3 2 2 4 systematic investigations of the relative free energies of binding of CHCl rS, we 3 derive a set of R U and van der Waals parameters that account for Cl Cl
experimental binding data. Although the complexes are of the van der Waals type, their electrostatic representation is also crucial for correct calculation of relative stabilities. Thus, the recognition of the ''best guest'' stems from a subtle balance of distance and time-dependent, cumulative noncovalent interactions between atoms of S and of L, which require an accurate representation. In