Besides utilizing the EVB method, the enzyme's catalytic effect can also be estimated using a modified semi-macroscopic version of the Protein-Dipole Langevin-Dipole (PDLD) method within the Linear Response Approximation (LRA) framework, termed PDLD/S-LRA-2000. This approach similar to our original PDLD/S-LRA method involves scaling the non-electrostatic term (C) (see below). In this method, the protein is considered a medium with a "dielectric constant" (𝜀 𝑖𝑚 ), signifying all implicitly treated contributions and involving thermodynamic cycles by adjusting the solvent's (water) dielectric constant ( 𝜀 𝑤 ) from its actual value 𝜀 𝑤 to 𝜀 𝑖𝑚 . Within the Linear Response Approximation (LRA) framework, 57 the PDLD/S free energies accommodate the effect of protein and solvent reorganization throughout the binding cycle, detailed in our previous works. In our current work, the binding free energy is expressed as: