The RMSD calculation between the MCSS of two ligand poses is the largest difference between Open-ComBind and ComBind. ComBind uses a MCSS strategy in which any two atoms can match in the graph regardless of atom type. We are unable to use this strategy with Open-ComBind as our RMSD calculation utilizes RDKit's 'CalcRMS' which requires that the input molecules have an exact substructure match. Therfore, our MCSS calculation enforces stringent atom type matching (excluding halogens which can all match each other). We additionally require that bond orders be identical for the bond to be included in the MCSS and that rings can only match other complete rings. These MCSS requirements enforce a stronger match between substructures of ligands and ensure that the scaffold of a congeneric series is placed in a similar location for all ligands.