where x 𝑖 represents the coordinates of i 𝑡ℎ conformer, the 0 𝑡ℎ conformer is the minimum energy conformer in respective potential energy landscapes, 𝜃 is the force field parameter set at that iteration, and OptMM(x 𝑖 , 𝜃) corresponds to the MM energy obtained via constrained minimization and 𝑑 𝐸 = 1 kcal/mol is a conversion factor to make the sum over deviations dimensionless. The weights 𝑤(𝐸 𝑄𝑀 ) in eq. 4 were applied to prioritize matching the torsion profile at the minima rather than the barriers. Boltzmann sampling favors low energy regions of state space, so agreement of potentials in low energy regions is typically of higher importance than agreement in high energy regions for thermodynamic measures. The choice of weights as a function of energy deviation from the minima 𝐸 𝑄𝑀 was similar to Parsley, and was based on a prior study that used a Boltzmann distribution with T = 2000 K (𝑘 𝐵 𝑇 ≈ 4.0 kcal/mol) to weight energies in torsion fitting and found that these weights led to the best performance relative to other choices. Thus, we used an energy cutoff as a function of QM energy difference from the minima 𝐸 𝑄𝑀 as follows: