Fig. 2.

Initial conformation of simulated systems. (A) The SARS-CoV-2 Mpro + inhibitor complex was inserted into the dPBC box. (B) The inhibitor was inserted into the dPBC box. The equilibrium structures of the SARS-CoV-2 Mpro + inhibitor and individual inhibitor in dPBC box systems were then used as the initial conformation of the FEP calculations. (C) The SARS-CoV-2 Mpro + inhibitor complex was inserted into the rPBC box. The equilibrium shapes of the SARS-CoV-2 Mpro + inhibitor in the rPBC box were then used as the initial conformation of the FPL calculations. In particular, the ligand was then forced to mobilize out of the binding cavity via external force $\overrightarrow{\overrightarrow{F}}$ during SMD simulations.