Molecular dynamics simulations and empirical valence bond (EVB) calculations on the best Kemp eliminase obtained in this work, together with some of its precursors, provided insight into the molecular mechanisms behind the enhancement achieved. Improved de novo activity is not linked to modifications in the catalytic machinery but, rather, to shifts in the conformational ensembles of both, crucial active-side residues and bound substrate, in such a way that productive conformations are promoted, while the population of non-productive conformations is decreased.