Figure 2.

Hybrid quantum mechanics/molecular mechanics (QM/MM) and QM-cluster approaches. (a) The hybrid QM/MM approach. Blue oval circle indicates the QM region, which includes the whole protein. Shown is the monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M^pro in complex with inhibitor N3 [Protein Data Bank (PDB) ID: 6LU7]. Red circle indicates the QM region, which includes the inhibitor (ligand, shown in orange sticks) and selected amino acid residues (shown in green sticks) in the active site that often involve in the catalytic mechanism. (b) The QM-cluster approach. This figure provides a conformation of the active site of the protease–inhibitor complex after density functional theory (DFT) geometry optimization. Shown in green-line representations are the active site residues and in cyan-stick representation is the inhibitor, the clovamide molecule. It clearly suggests that a covalent bond is formed between one carbon on the quinone ring and the sulfur atom in the C145 catalytic residue. For details, refer to Ye et al.⁵⁹ Adapted with permission from⁵⁹.