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 applied weights w(E QM ) in equation 6 prioritize matching the torsion profile at energy minima since Boltzmann sampling favors low-energy regions in state space. w(E QM ) =