Furthermore, the flexibility of BespokeFit and its interface with QCEngine allows us to investigate the balance between accuracy and speed for a range of QC, semi-empirical and machine learning based reference data generation methods. Further work will be required to investigate the optimal combinations of methods to generate and refine the reference potential energy surfaces , and to determine whether improvements in reference data always lead to improved binding free energy estimates, as we saw here. It seems likely that in some cases sampling, rather than force field quality, may be a limiting factor.