Path sampling methods represent a class of enhanced sampling approaches that enable comprehensive exploration of the kinetic properties in biological systems, encompassing phenomena such as receptor-ligand binding and unbinding, protein folding and unfolding, and substantial conformational changes in complex biological systems. The Markovian milestoning with Voronoi tessellations (MMVT) approach in MD simulations partitions the phase space of the receptor-ligand complex into distinct regions called "Voronoi cells" . Independent and parallel MD simulations are carried out within each Voronoi cell, with the ligand incrementally displaced from the bound state. This approach is implemented in the computational software toolkit, Simulation Enabled Estimation of Kinetic Rates v.2 (SEEKR2) , which is further discussed in section 2.2. Estimation of drug-target residence times of pharmaceutically relevant biomolecular complexes remains difficult for MD-based approaches. However, SEEKR2 has recently succeeded in estimating close-to-experiment residence times for JAK2/STAT5 axis inhibitors with extended residence times (hours or longer) within the target .