Our results support, overall, that FuncLib predictions may provide an efficient computational methodology to speed up directed evolution by guiding screening to regions of the sequence space that are safe and catalytically-relevant. We have further shown here that the experimental free energy barriers for the optimized eliminases can be reproduced to within ~2 kcal•mol -1 by the empirical valence bond calculations. This is impressive in light of the very small changes in activity involved (from a thermodynamic perspective, Table ) and thus the associated challenges of optimizing Kemp eliminase activity using electrostatics alone. We note that other computational studies of Kemp elimination also report activation free energies with deviations within this range or up to several kcal•mol -1 from experiment. In addition, whereas we and others have been able to obtain high fidelity with experimental values across a wide range of enzymes and enzyme variants even in the case of far more complex systems than the current Kemp eliminase. This makes EVB useful as a predictive tool for systems where the changes in energy involved as not as subtle as in the case of Kemp elimination.