In one dimension, these milestones are concentric spheres with radii based on the increasing distance between the COM of the receptor-ligand binding site and the ligand (Figure ). Independent MD and BD simulations are performed; reflective boundary conditions are imposed within the MD Voronoi cells (Figure ). Once the simulation finishes, we can use milestoning theory to obtain the receptor-ligand unbinding rate (k off ) and the addition of BD theory to obtain the receptor-ligand binding rate (kon) (Figure ). Thermodynamic parameters can then be obtained from the kinetic rates, kon and k off .