Previous studies on CDs ( -CD, -CD, and mono-3-carboxyproponamido-CD) report two distinct bound states for each hostguest pair. The first bound state, called the "primary orientation", has the guest polar group (i.e., alcohol, ammonium, carboxylate) towards the glucose subunits primary alcohols, while the "secondary orientation" has the guest polar group towards the secondary alcohol (Figure ). Though a possible third "surface orientation"/binding mode has been speculated to exist, it may be this is a transition needed for the guest to flip from primary to secondary phase orientation or vice-versa . The difference in binding free energy for the two main orientations has been reported as being about 2 kcal/mol and up to 5 kcal/mol using several different force fields , with this of course also depending on the guest. The same report suggested that using GAFF v2.1 better models the flexibility of -CD compared to the SMIRNOOFF99Frosst and GAFF v1.7 force fields.