(A) Division of the QM/MM system. Atoms in blue color were treated as QM part. The boundary carbon atoms colored in red were treated with the improved pseudobond parameters. All of the other atoms were considered as the MM subsystem. (B–F) Optimized geometries for the key states during the reaction process for the inhibition of proteasome (β5 active site) by EPX. The geometries were optimized at the QM/MM(B3LYP/6-31G*:AMBER) level. The key distances in the figures are in Å. Carbon, oxygen, nitrogen, and hydrogen atoms are colored in green, red, blue, and white, respectively. The backbone of the protein is rendered as ribbon and colored orange. The QM atoms are represented as balls and sticks and the surrounding residues are rendered as sticks or lines. Figures to be discussed below are represented using the same method.