Equation 1: PI: Percentage of interaction with a binding site residue. min (PI) and max (PI): the lowest and highest Percentage of interactions, in compared hotspots, respectively. ΔEa FMO : interaction energy with a binding site residue. min(ΔE FMO ) and max(ΔE FMO ): the lowest and highest interaction energy, in compared hotspots, respectively.