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

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 performed on the macrocyclic ligand cryptophane-E (L) and its L·S complexes with three tetrahedral guests (S=CH2Cl2, CHCl3, and CCl4) in the gas phase 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*Cl and εCl parameters for the Cl atoms of S lead to a preference for CCl4, in contrast to the selectivities observed experimentally in solution (CHCl3 > CH2Cl2 > CCl4). Based on systematic investigations of the relative free energies of binding of CHCl3/S, we derive a set of R*Cl and εCl van der Waals parameters that account for 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 addition, even in a weakly polar solvent, like chloroform, solvation effects are shown to modulate the recognition of the neutral substrates.