In parallel to the ongoing advances in various enhanced sampling techniques for describing the conformational properties of biomolecular systems , there is also ever-increasing interest in using multi-scale approaches to describe chemical reactions in biological systems . Here, Warshel's empirical valence bond (EVB) approach provides a particularly powerful tool, as it can predict free energies for chemical reactions in a wide range of complex systems, often with chemical accuracy . This approach has been described in detail elsewhere , but, in brief, it is a classical approach in which different force fields are parameterized to describe different chemical states of interest, and this is then transferred to a quantum mechanical valencebond based framework by mixing these force fields using free energy perturbation/umbrella sampling (EVB-FEP/US). In the EVB approach, chemical reactivity is modelled by use of Morse potentials to describe the bonds that change along the reaction coordinate, as well as a Buckingham-type potential to describe van der Waals interactions between reacting atoms, and prevent system instabilities as bonds change along the reaction coordinate.