We then demonstrated that, as expected, the method reproduced fragment binding modes. We found that GCNCMC sampled the two binding modes of simple fragments in a host-guest system with our simulations showing the guest molecules binding in an orientation in line with experimental and other reported data. A more detailed examination of Toluene binding to T4L99A showed that the method successfully replicated the four binding modes with populations consistent with previously published studies. GCNCMC titrations were then used to calculate the binding affinities of a series of small molecules to the host molecule, β-cyclodextrin, and the protein systems T4L99A and MUP1. We found that for the relatively simple βCD test case, a good correlation with experimental data, and an orthogonal computational method (ABFE calculations with restraints), was observed. This agreement with a well-established method provides solid validation and is important to demonstrate when developing a new free energy approach. Likewise, similar behavior was seen in both protein systems.