The scaling factor C for the non-electrostatic contribution, critical in our analysis, was treated with care following our 2000 benchmark study. This C factor is not a universal constant but is specific to the studied system, influenced by a complex balance of thermodynamic contributions like van der Waals interactions, hydrophobic effects, water penetration, and configurational entropy changes, further explained in ref. For the current study, we determined an optimal C value of 0.70, which effectively calibrates calculated binding affinity with experimental observation (vide infra).