In terms of correlation between calculated and experimental values (Figure ), there is a weak correlation between calculated and experimental activation free energies (R 2 = 0.27, calculated using linear regression analysis, note that we have removed the GNCA4-WT from this correlation as this is not a FuncLib predicted structure). This is, however, due to the fact that the energy differences involved are (again from a computational perspective) so small that even small deviations from the experimental value will lead to weak correlation with experiment. In terms of the comparison between the Rosetta score obtained from FuncLib (Table ) and the experimental activation free energy, we obtain essentially no correlation with experiment (R 2 = 0.12, again omitting the GNCA4-WT for the same reason as above), which likely reflects the fact that the FuncLib ranking does not include any information about the substrate or transition state and is based exclusively on stability of the scaffold. Similarly, for the variants where we have crystal structures available (GNCA4-WT, GNCA4-2, GNCA4-12 and GNCA4-19), we obtain similar correlation between calculated and experimental activation free energies (R 2 = 0.38), although this is a correlation over only 4 enzyme variants and the energy differences between calculated and experimental values is always within ~1 kcal•mol -1 indicating again that the weak correlation coefficients in this specific case are mainly due to the very small energy differences involved (which are within the resolution of EVB and other QM/MM methodologies) rather than a problem with the method.