The host molecule is initially parameterized using the q4md-CD force field 113 , while the guest ligands are parameterized using the general Amber force field (GAFF) 114 . q4md-CD force field has been designed to accurately represent the geometrical, structural, dynamical, and hydrogen bonding aspects of heterogeneous cyclodextrin-based systems 113 . q4md-CD force field incorporates geometrical parameters from the Amber99SB force field to describe protein residues and GLYCAM04 for carbohydrate and organic components (if available). Partial atomic charges are derived using the R.E.D. tools 115 , while scaling factors of 1.2 and 2.0 are imposed for the 1-4 electrostatic and 1-4 van der Waals interactions, respectively. The q4md-CD force field has demonstrated better agreement with experimental findings compared to GAFF for cyclodextrin molecules . Subsequently, the complexes are solvated with the TIP3P water model and subjected to a non-bonded cut-off distance of 9 Å, and long-range electrostatic interactions were treated with the particle mesh Ewald (PME) method . The relatively smaller size of the host-guest complexes necessitates the division into two regions. We treated the ligand molecules quantum mechanically using the Becke-3-parameter-Lee-Yang-Parr (B3LYP) functional 120 , and correlation consistent polarized valence triple zeta (cc-pVTZ) 121 basis set in the QM region. The host molecule is assigned the QM2 region where the semi-empirical tight-binding method (GFN2-XTB) is employed. For each of the host-guest complexes, 14 CV-based milestones are defined as concentric spheres and are located at distances of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, and 14.0 Å respectively from the center of mass (COM) of the host. Starting structures for the SEEKR2 simulations are obtained using the steered molecular dynamics (SMD) simulations, where a moving harmonic restraint of 50,000 kJ mol -1 nm -2 is applied over the course of 50 ns. Identical CV definitions and milestone spacings have been implemented in the current study as in the previous SEEKR2 implementation , facilitating a comparison between the two methodologies. SEEKR2 simulations with the QMrebind-reparameterized force field parameters are run with same milestone spacings for all the complexes. A total of 50 ns of MD simulations are run within each Voronoi cell, totaling a simulation time of 700 ns for 14 Voronoi cells. To obtain statistically meaningful results and assess the reproducibility and robustness of the simulations, three replicas of SEEKR2 simulations are performed for each complex, totaling a simulation time of 2.1 µs. Experimental values for the unbinding rates for the seven host-guest complexes, along with the k off rates estimated by the SEEKR2 framework, with the QMrebindreparameterized and generic force field parameters, are provided in Supplementary Table .