the long-timescale protocol, and the splitting protocol (an adaptive sampling method). These protocols are applied with a key goal in mind: to elucidate novel ligand binding sites and mechanisms for the three aforementioned proteins that are essential to the life cycle of SARS-CoV-2: ADRP, 3CL-Pro, and PL-Pro. We also employ different free energy protocols in order to determine the pros and cons of each method and discuss their domains of applicability and limitations.