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 that we call MME55. The set contains 10 different enzymes, representing eight transition metals, both open and closed shell systems, and system sizes of up to 116 atoms. We use four 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. Jacob's ladder is reproduced for the whole set based on averaged mean absolute (percent) deviations, with the double hybrids SOS0-PBE0-2-D3(BJ) and revDOD-PBEP86-D4 standing out as the most accurate methods for the MME55 set. The range-separated hybrids ωB97M-V and ωB97X-V also perform well here and can be recommended as a reliable compromise between accuracy and efficiency; they have already been shown to be robust across many other types of chemical problems, as well. Despite the popularity of B3LYP in computational enzymology, it is not a strong performer on our benchmark set, and we discourage its use for enzyme energetics.