Computational studies on TIM have been pursued vigorously, because of their potential to provide a description of the events at the enzyme active site not accessible to examination by experimental studies. The many X-ray crystal structures for TIM from various organisms, and with a variety of ligands bound, provide valuable starting points for computational studies that model the experimental activation barrier for conversion of enzyme- bound substrate to product. It is important to test these models with larger bodies of experimental data in order to advance towards computational models that are able to fully reproduce the operation of TIM and other highly proficient enzymes. We have therefore challenged the empirical valence bond (EVB) approach to model the results of recent mutagenesis studies on TIM, with a focus on substitutions of the amino acid side chains shown in Figure (using yTIM numbering throughout this work).