Molecular modeling was conducted with Maestro (Schrödinger Release 2023-1, Schrödinger LLC, New York, NY, 2023) and OPLS4 force field. The co-crystal structures of the analogous inhibitors were downloaded from the PDB and prepared using Protein Preparation Wizard 65 : bond orders were assigned and hydrogens replaced, zero-order bonds to the metals were created, the missing side chains and loops were added with Prime 66,67 and Epik was applied to generate the small molecule ionization states, all crystal waters were preserved, H-bonds were optimized with sampled water orientations and PROPKA, and energy minimization was conducted (0.3Å heavy atom RMSD convergence). The aligned analogous structures were visually analyzed, and we decided to use 6UT0 and 8AFB for building our initial protein-ligand configuration. The existing ligand was replaced with studied inhibitor (adagrasib in 6UT0 with GDC-6036; BI-0474 in 8AFB with LY3537982), which was described using the default OPLS4 force field parameters. The initial conformation of LY3537982 was taken from the output of the QM Conformer & Tautomer Predictor (see section QM calculations). In the 8AFB structure the carbonyl group of the LY3537982 appeared to overlap with one of the crystal waters at the S-IIP (HOH: 344), which was therefore deleted. In the selected protein structures, we reverse mutated the S51; L80 and S118 back to the native cysteine residues (6UT0), and S118 in case of 8AFB. Thr2 at the N-terminus was acetylated, as well as the C-terminal residue Lys169 (6UT0) or Lys165 (8AFB). Both new complexes were run through Protein Preparation Wizard 65 , and the energy minimization was conducted twice with the 0.3Å heavy atom RMSD convergence setting.