Using the three sets of reference values to test the DFAs as before, we show results for the whole ENZYMES22 set in figure . As seen for the subset used in the test set previously, the differences in the MADs with the three reference lev- Based on these results we can conclude that for models of organic enzymes and their associated BHs and REs, the additional accuracy of CPS(6,7) is not required, and the lower-cost alternative CPS (5,6) is accurate enough to use as reference values for large models-extending the limits of system sizes on which we can conduct reliable benchmark studies. We also briefly note the strong performance of CAM-B3LYP-D3(BJ), which was not previously tested in our original study using the ENZYMES28 set. This is a notable and surprising result, as it has not been shown to be particularly better compared to global hybrids in a more comprehensive study of main-group thermochemistry. We conclude this work by presenting the DLPNO-CCSD(T 1 )/CPS(6,7)/CBS (3,4) reference values (table 2) for the EN-ZYMES22 set calculated herein so that they can be used for future benchmarking We provide a comparison of the functional MADs calculated from the old DLPNO-CCSD(T 0 )/TightPNO-based references and new DLPNO-CCSD(T 1 )/ CPS(6,7)/CBS (3,4) references in figure of the Supporting Information, and note some minor changes in the DFA rankings. Against the old references, SOS0-PBE0-2-D3(BJ) was clearly the best double hybrid but it is almost indistinguishable from the (rev)DOD/DSD functionals when compared to the updated references, while CAM-B3LYP-D3(BJ) was not as separated from the other best hybrids against the old references as it is against the new ones. However we note that the best hybrids and double hybrids all perform well against both sets of references, with MADs generally around 1 kcal/mol, so small differences in the magnitudes and rankings are unlikely to be statistically significant and a number of the tested methods can be recommended as reliable.