Ensemble Simulations of 2-Hydroxypropyl-β-cyclodextrin Complexes with All-Atom Molecular Dynamics Simulations

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.
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. Improved binding proportional to the added side chains was found. To show the applicability of the HP-β-CD force field, an ensemble of simulations guided by experimentally determined distributions of isomers from mass spectrometry was generated. The results for ibuprofen and ketoprofen shows that acceptable accuracy in free energies of binding can be obtained with ensembles.

Munk JT, Nygaard-Thomsen S, Stokholm TRB, Langhorn MR, Steinmann C. Ensemble Simulations of 2-Hydroxypropyl-β-cyclodextrin Complexes with All-Atom Molecular Dynamics Simulations. ChemRxiv. Cambridge: Cambridge Open Engage; 2022;