Force Field Parameterization for the Description of the Interactions between Hydroxypropyl-β-Cyclodextrin and Proteins

[Image: see text] Cyclodextrins are cyclic oligosaccharides, widely used as drug carriers, solubilizers, and excipients. Among cyclodextrins, the functionalized derivative known as hydroxypropyl-β-cyclodextrin (HPβCD) offers several advantages due to its unique structural features. Its optimal use in pharmaceutical and medical applications would benefit from a molecular-level understanding of its behavior, as can be offered by molecular dynamics simulations. Here, we propose a set of parameters for all-atom simulations of HPβCD, based on the ADD force field for sugars developed in our group, and compare it to the original CHARMM36 description. Using Kirkwood–Buff integrals of binary HPβCD–water mixtures as target experimental data, we show that the ADD-based description results in a considerably improved prediction of HPβCD self-association and interaction with water. We then use the new set of parameters to characterize the behavior of HPβCD toward the different amino acids. We observe pronounced interactions of HPβCD with both polar and nonpolar moieties, with a special preference for the aromatic rings of tyrosine, phenylalanine, and tryptophan. Interestingly, our simulations further highlight a preferential orientation of HPβCD’s hydrophobic cavity toward the backbone atoms of amino acids, which, coupled with a favorable interaction of HPβCD with the peptide backbone, suggest a propensity for HPβCD to denature proteins.