to study the effects of box size on the association constant. These simulations are conducted using the PLUMED package together with the CP2K code . Association constants are obtained from the free energy surface (FES) using the method described by Chialvo et al. . More details of this method are provided in the SI. The integration cutoff of the radial distribution function, r c in Equation S11 is taken as half of the edge length of the respective simulation boxes, i.e. ∼6.10-6.30 Å for boxes #5 and #6 and ∼10.00-10.80 Å for boxes #4 and #7 (see Table ). r i in the same equation is set to ∼2.8 Å in all biased simulations corresponding to the distance of the first minimum in FES.