2-Hydroxypropyl-β-cyclodextrins (HP-β-CDs) ability to form inclusion complexes with lipophilic compounds is important both to treat Niemann Pick Type C disease and as part of a more general drug-formulation as a drug carrier. Theoretical studies of inclusion complexes with classical molecular dynamics simulations of HP-β-CDs are hampered by the fact that there are more than 2 million possible isomers to consider. We construct a general GLYCAM06 (Kirschner, K. N. et. al., J. Comput. Chem. 2007, 29, 622–655) compatible force field to treat all possible isomers of HP-β-CDs and investigate the effect on free energies of binding obtained from the MM/GBSA approach when increasing the degree of substitution. We find improved binding proportional to the added side chains. To show the applicability of the HP-β-CD force field, we generate an ensemble of simulations guided by experimentally determined distributions of isomers from mass spectrometry. Our results for ibuprofen and ketoprofen shows that acceptable accuracy in free energies of binding can be obtained with ensembles generated from around 40 isomers, but this is dependent on the guest molecule. We also investigate a simple linear relation between molecular log(P ) and free energy of binding for inclusion complexes of HP-β-CD. The linear model is promising but we find that the accuracy is too dependent on a single simulation. The presented force field and computational approach should provide for more realistic simulations.