The simulation data suggested that GDC-6036 forms its key interactions with Lys16, Glu62, Asp69, His95 and Tyr96 (Figure ). Lys16 makes H-bond interaction with the carbonyl oxygen, a commonly observed interaction with the acrylamide warhead containing inhibitors. His95 of the a3-helix is making H-bond interaction to the quinazoline of GDC-6036, as well as p-cation interaction to its positively charged 1-methylpyrrolidine motif. In addition, the latter moiety is also interacting with Glu62. While the Tyr96 residue, located at the base of the SII-P, forms hydrophobic interactions with GDC-6036, including p-p stacking with the quinazoline. On the a2-helix side of KRAS, a highly stable H-bond interaction between Asp69 and the amino group of the 6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl moiety was observed throughout the simulations. Adjacent to the pocket, the Tyr64 residue appears to shield GDC-6036 from solvent exposure by introducing its side chain as a lid on top of the inhibitor (Figure -D, Figure ).