Molecular modeling was conducted with Maestro (Schrödinger Release 2021-4, Schrödinger LLC, New York, NY, 2021) and OPLS4 force field. All publicly available KRAS structures with SII-P binders were downloaded from RCSB Protein Data Bank and prepared and energy minimized using Protein Preparation Wizard 62 , adding the missing side chains and loops with Prime and keeping the crystal waters within 5Å of the ligands (deleting the other waters). We deleted closely residing co-crystallized excipients near the SII-P from the structures, which would have potentially impacted WaterMap results. We excluded the two structures from the SII-P binder analysis (PDB IDs: 7U8H and 8AFD) that contain SII-P binding fragments that are co-crystallized with a secondary site covalent small-molecule and with a different position 12 mutant (KRAS(G12V, S39C-BIT)+GDP). 50