A and B, this translates into four separate calculations, in which the free energy difference between the Hamiltonian of molecule A and B in vacuum (∆G A,vac MM→QM and ∆G B,vac MM→QM ) and in solution (∆G A,solv MM→QM and ∆G B,solv MM→QM ) between both levels of theory is calculated. In this work, we systematically study the use of the ANI-2x NNP as the high-level potential in indirect free energy calculations.