Figure 1: Thermodynamic cycle for BPMFs.

Milestone thermodynamic states are labeled with letters in parentheses and expressions for the reduced potential energy. ${\beta }_T^{-1}=k_B\left(300\text{\hspace{0.17em}K}\right)$ and ${\beta }_H^{-1}=k_B\left(600\text{\hspace{0.17em}K}\right)$ are inverse temperature factors for the target and high temperatures, respectively. U_T (·) and U_S(·) denote potential energies for the target and sampling force fields, respectively. These potential energies include molecular mechanics terms and the implicit solvent model. Ψ_g(·) is the potential energy due to receptor-ligand interaction grids. Arrows with orthogonal lines indicate multiple intermediate thermodynamic states. For BPMF calculations, configurations are sampled from thermodynamic states with the rounded boxes and from their intermediates.