where Δ𝐺 #52<$ is the binding free energy of VMetaD, 𝑅 is the gas constant, 𝑇 is the temperature of the system, 𝑉 ' is the standard volume (1660 Å 3 ), and 𝑉 :472 is the volume of the protein included in the sphere restraint. Protein volume inside the sphere was calculated using the double cubic lattice method 61 available in GROMACS. To compute the Δ𝐺 #52<$ , we reweighted the computed free energy surface using the Tiwary-Parrinello algorithm , removing the initial 200 ns of trajectory on CVs that allow the precise definition of the bound and the unbound states. Following ref. the distance 𝜌 and the coordination number 𝑐, between the set of the ligand atoms A and the set of the protein atoms B, were selected as: