To demonstrate the capability of DMFF, six relative free energies (∆∆G) are selected from TNKS2, which is one of the most popular protein-ligand binding affinity benchmark sets. As a proof of concept, we try to optimize the GAFF2 BCC parameters against the selected data points. The loss function is defined in Eqn. 18 and the steepest gradient descent algorithm is utilized for the optimization.