The estimated TightPNO approach also cuts costs, but comes with a greater reduction in accuracy-the MAD is still below 1 kcal/mol, but the error for Hc 1RE2 is almost twice that at 1.922 kcal/mol. However, this is likely an issue specific to the Hc enzyme. The DLPNO scheme involves treating only strongly interacting pairs at the Coupled Cluster level, while weakly interacting pairs are calculated with MP2. As Liakos and Neese have pointed out, the MP2 correlation energy of the Cu 2 O 2 core is wildly inaccurate compared to CCSD(T) and LPNO-CCSD, particularly for the peroxo configuration which is formed in the second Hc RE. In the calculations with looser T CutP N O values, more pairs are considered weak pairs, and therefore MP2 has a stronger influence on the overall energy. This leads to larger than expected changes between the T CutP N O = 10 -5 and 10 -6 results, and the PNO extrapolation overshoots the standard TightPNO correlation energy. Across the other four REs the results are much better (the MAD across these steps is only 0.455 kcal/mol).