Modeling the binding of covalent inhibitors with their targets requires characterization of both the non-covalent and covalent binding free energy steps. Multiscale QM/MM calculations are useful in this regard since they allow chemical processes to be modeled-particularly, the chemical bond formation step between the target residue in the protein and an inhibitor. To estimate the covalent binding free energy contribution of the M pro inhibitors studied, we performed ONIOM (QM:MM) calculations on the model systems. Using this approach, we calculated the relative Gibbs energy difference between the equilibrium non-covalent complex and the covalent complex. Our results for the covalent binding free energy of the inhibitors to the M pro target are summarized in Table . The results indicate that the reaction leading to the formation of the covalent bond between Cys145 of the M pro and the inhibitors is moderately exergonic. For irreversible Michael acceptor inhibitors of the M pro , covalent binding reaction energies as high as -28 kcal/mol have been predicted. We found that among the complexes studied, the reaction free energy for adduct formation is greatest for the MI-30 inhibitor bound complex (ΔGcovalent = -10.5 kcal/mol). The covalent binding free energy calculated for the other adducts are -6.0 kcal/mol, -8.3 kcal/mol and -6.8 kcal/mol, for the inhibitors 11a, GC373, and PF-231, respectively (Table ). These results suggest that the inhibitors 11a and PF-231 engage more reversibly towards the M pro target than GC-373 and MI-30 inhibitors. The relative magnitude of the covalent binding free energy predicted for these inhibitors is in line with their reversible characteristics as observed by experiment. In addition, our predicted covalent binding energy results for the M pro -PF231 and M pro -11a inhibitor bound adducts are in agreement with recent multiscale QM/MM studies that investigated the mechanism of covalent inhibition of the M pro target by these compounds. Interestingly, we observe different covalent binding energies for the inhibitors 11a, GC373, and MI-30 which share a common warhead (i.e., an aldehyde functional group). This suggests that there are a range of factors beyond warhead type that can influence the binding energetics of reversible covalent inhibitors to their targets. Knowledge of both covalent and noncovalent binding free energy contributions is essential in determining the overall binding energetics of covalent inhibitors to their enzyme targets.