Empirical valence bond (EVB) simulations of wild-type SHP1 and variants were performed at the phosphoenzyme intermediate preceding the rate-limiting hydrolysis step, using the same protocol as in prior work, using the OPLS-AA force field, and the TIP3P water model. PDB ID 4GRZ was used to describe the closed catalytic state, while the different variants were generated in silico by truncation of the corresponding side chains or substitution for the highest probability rotamer using the Dunbrack 2010 Rotamer Library. A list of ionized residues in our simulations (necessary for describing the system using the Surface Constrained All Atom Solvent Model, SCAAS, (see prior work ) is found in Table . All simulations were performed in 30 individual replicates per system, with each trajectory involving an initial 30 ns of equilibration followed by 10.2 ns of EVB simulation (51 EVB mapping frames x 200 ps simulation time per frame), as in prior work, to a total simulation time of 1.206 μs per system and 4.824 μs cumulatively across all systems. Convergence of the EVB equilibration runs is shown in Figure . The EVB mapping parameters shown to obtain calculated activation free energies are identical to those used in prior work.