In which superscript 'p' and 'w' refer to protein and water environments, respectively. 'Q' represents the substrate atoms' charge distribution, which alternates between its actual charge distribution and zero throughout the binding cycle (see ref. 40 and 55). The <> 𝑄 notation indicates an average over configurations from MD simulations with the specified Q. The non-electrostatic term accounts for binding free energy from hydrophobic effects, van der Waals, water penetration and entropy contribution.