where P i is the probability of a particular outcome ; here, we use to indicate a positive sign or a negative sign for the predicted free energy change. So P positive is the fraction of positive sign predictions, P negative is the fraction of negative sign predictions, and P neutral is the fraction of neutral sign predictions (which were somewhat frequent as a few participants predicted a free energy change of exactly 0 for some transitions). For example, for SM25_micro001, given the predictions we received, the The MAE of each molecule separated by method category suggests the most challenging molecules were different for each method category. It is difficult to draw statistically significant conclusions where there are large overlapping confidence intervals. The QM+LEC method category appears to be less accurate for the majority of the molecules compared to the other method categories. QSPR/ML methods performed better for isoxazoles (SM41-SM43) and 1,2,3-triazoles (SM44-SM46) compared to the other two method categories. Physical QMbased methods performed poorly for acylsulfonamides (SM26 and SM25). (B) Error distribution for each molecule over all prediction methods. SM25 has the most spread in pK a prediction error.