Free energy calculations (FEP and TI): Conformational preference of a cyclodextrinic [2]catenane: A case study

The two most common computational methodologies for estimating free energy differences (Free Energy Perturbation, FEP and Thermodynamic Integration, TI) have been used to study the conformational preference of a cyclodextrinic [2]catenane. A strategy based on the use of several FEP simulations and an averaging of the results has been shown as the best approach for properly evaluating the conformational Delta G in this large and flexible system. The stereoisomer (conformer) where the (2,6-di-O-methyl)-beta-cyclodextrin is over the bitolyl station is shown to be preferred by about 1 kcal/mol, in agreement with the experimentally available data.