How to simulate affinities for host-guest systems lacking binding mode information: application to the liquid chromatographic separation of hexabromocyclododecane stereoisomers.

A novel approach for the simulation of host-guest systems by systematically scanning the host molecule's orientations within the guest cavity is presented along with a thermodynamic strategy for determining preferential binding modes and corresponding optimal interaction energies between host and guest molecules. By way of example, the elution order of hexabromocyclododecane stereoisomers from high performance liquid chromatography separation on a permethylated β-cyclcodextrin stationary phase has been computed using classical molecular dynamics simulations with the explicit solvents water and acetonitrile. Comparison of estimated with experimental separation data reveals remarkable squared coefficients of correlation with R(2) = 0.87 and a very high correlation R(LOO2) = 0.72 using the leave-one-out cross-validation method and water as solvent. In particular, the approach presented shapes up as very robust in terms of the evaluated time range under consideration, reflecting well thermodynamic equilibria. These and further observations correlating with experimental results suggest the suitability of the underlying force fields and our multi-mode approach for the estimation of relative binding affinities for host-guest systems with unknown binding modes.