We have presented a new general GLYCAM06 compatible parameterization of the side chains in 2-hydroxypropyl cyclodextrin that enables the use of the more than 2 million isomers in for example β-cyclodextrin. Our parameterization involved generating partial atomic charges for each of the possible substituted side chains thereby taking their local chemical environment into consideration even differences were small. When we applied this new parameterization to obtain free energies of binding with the MM/GBSA, we found that free energy of binding became more favorable (more negative) as the degree of substitution was increased. We investigated four molecules with increasing log(P ) that all saw in increase in predicted free energies of binding as the degree of substitution was increased due to a supposedly elongation of the cavity.