For computing kinetic and thermodynamic properties for receptor-ligand complexes, we have employed different theoretical frameworks to model certain regions of the biomolecular complex under study. Specifically, we applied a higher level of theory (i.e., high-level QM and low-level QM2) to model the active site of the complex and obtain optimized point charges of the ligand while bound at that site while utilizing classical mechanics to model the remaining protein (Figure ). This multiscale approach allows for a more precise and efficient representation of the molecular system within the bound state, which may improve accuracy when modeling the binding and unbinding process. ORCA, a versatile quantum chemistry package that offers a wide range of electronic structure methods, enables the application of different theoretical frameworks for different regions of a molecular system . In its latest release, i.e., ORCA 5.0, new features include the three-layered (QM-QM2-MM) ONIOM method with electrostatic and mechanical embedding, covalent bond boundary definitions between the QM and QM2 regions, and automated detection of system topologies with link atoms . QMrebind integrates the ORCA QM engine for reparameterizing force field parameters for receptor-ligand complexes.