As a realistic exemplary application, we computed the reaction energy (∆E rxn ) and forward barrier height (∆E ‡ ) for a 632-atom active-site model of methyl transfer catalyzed by the enzyme catechol O-methyltransferase. Using the ωB97X-D functional, in conjunction with an iterative implementation 54 of a dielectric continuum model, we obtain ∆E rxn = -18.4 kcal/mol using def2-TZVP versus ∆E rxn = -18.0 kcal/mol with 6-311G(2df,p), and ∆E ‡ = 14.6 kcal/mol (def2-TZVP) compared to 13.8 kcal/mol [6-311G(2df,p)]. Differences between the two basis sets are well within the intrinsic accuracy of the functional itself, 10 but the def2-TZVP calculations are 1.9× more expensive. This is a significant reduction given that the ωB97X-D/def2-TZVP calculations require 2,841 h of aggregate computing time on a single 48-processor node.