Table 3. Embedding Energy Prediction RMSE (kcal/mol) and Execution Times (s) for the SARS-CoV-2 Mpro Complex with PF-00835231^a.

method	EFull	EStatic	EInduced	t
B3LYP/cc-pVTZ+OPLS-AA	3.800	3.018	1.486	6802
PBE0/cc-pVTZ	0.214	0.217	0.022	6884
B3LYP/cc-pVDZ	0.639	0.504	0.307	2261
BLYP/6-31G*	0.655	0.539	0.326	429
ML/MM qMBIS	1.484	1.394	0.560
ML/MM MBIS	1.490	1.398	0.549
ML/MM ⟨χMBIS⟩	1.760	1.644	0.561
ML/MM ⟨qMBIS⟩	2.046	1.926	0.561
ML/MM	2.046	1.941	0.567	0.05
GFN2-xTB	4.342			0.7
AM1	10.330			0.9
PM3	10.663			0.9

^aThe systematic error was removed by subtracting the mean in all cases (see text). B3LYP/cc-pVTZ+OPLS-AA - energies calculated with B3LYP/cc-pVTZ but using charges from the OPLS-AA force field instead of ffSB14; ML/MM - prediction based on the model trained in section 3.3; ML/MM MBIS - ML/MM with q_core, q_val, and s taken directly from MBIS partitioning; ML/MM q_MBIS - predicted charges replaced by their exact MBIS values; ML/MM ⟨χ_MBIS⟩ - electronegativities replaced by their average MBIS values (see SI, section S7); ML/MM ⟨q_MBIS⟩ - charges replaced by their average MBIS values. The execution times are single SCF time in the case of DFT and semiempirical methods and time to calculate the embedding energy in the case of ML/MM (using a single CPU core).