Because the RCE are the energies relative to the structure with the lowest energy and, by common convention, the lowest energy conformation is assigned the relative energy value of 0. Consequently, the difference between the simulation result and the target value is always 0 for this conformation and the corresponding weight ω MM 1 is also set to 0 in every approach. By setting ω MM 1 = 0, it is ensured that the total amount of weight assigned for this property (i.e.