AbstractThe SEAM method, which models a transition structure as a minimum on the seam of two diabatic surfaces represented by force field functions, has been used to generate 20 transition structures for the decarboxylation of orotidine by the orotidine‐5′‐monophosphate decarboxylase enzyme. The dependence of the TS geometry on the flexibility of the system has been probed by fixing layers of atoms around the active site and using increasingly larger nonbonded cutoffs. The variability over the 20 structures is found to decrease as the system is made more flexible. Relative energies have been calculated by various electronic structure methods, where part of the enzyme is represented by a force field description and the effects of the solvent are represented by a continuum model. The relative energies vary by several hundreds of kJ/mol between the transition structures, and tests showed that a large part of this variation is due to changes in the enzyme structure at distances more than 5 Å from the active site. There are significant differences between the results obtained by pure quantum methods and those from mixed quantum and molecular mechanics methods. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009