Benchmarking Density Functional Theory Methods for Metalloenzyme Reactions: The Introduction of the MME55 Set

We present a new benchmark set of metalloenzyme model reaction energies and barrier heights, which we call MME55. The set contains eleven different enzymes, representing eight transition metals, both open and closed shell systems, and system sizes of up to 116 atoms. We use three DLPNO-CCSD(T)-based approaches to calculate reference values, against which we then benchmark the performance of a range of density functional approximations with and without dispersion corrections. Dispersion corrections improve the results across the board, and triple-ζ basis sets provide the best balance of efficiency and accuracy. While Jacob’s Ladder is reproduced for the whole set based on averaged mean absolute deviations, hybrid DFT is preferred over double hybrids for copper- dependent enzymes, where MP2 correlation seriously adversely affects the results. Despite the popularity of B3LYP in computational enzymology, it is not a strong per- former on our benchmark set, and we discourage its use for enzyme energetics. Instead, we recommend the range-separated hybrids ωB97M-V and ωB97X-V combined with the def2-TZVPP basis set for applications, as they are a great compromise between accuracy and efficiency and have al- ready been shown to be robust across many other types of chemical problems.