To rationalize our findings related to the WT isoform binding and specificity of the two inhibitors (Table ), we conducted molecular dynamics (MD) simulations with non-covalently bound adagrasib and sotorasib in the SII-P with KRAS(WT) and NRAS(WT) (Figure ). These simulations suggest that the observed key-interactions are mainly isoform-agnostic for sotorasib, while this is not the case for adagrasib (Figures ). The most significant discrepancy between the inhibitors is observed for interactions with the position 95 (Figures and S13-S14). Adagrasib displays high interaction frequency with KRAS His-95 (156%; multiple simultaneous interactions add up to over 100%) (Figure ). This interaction frequency is dramatically diminished when the residue in this position is leucine, as found in NRAS. In contrast, sotorasib's interaction frequency with position-95 is slightly elevated with L95 (15%) in comparison to H95 (9%). These observed interactions of both inhibitors with KRAS H95 and NRAS L95 are consistent throughout the conducted simulations (Figure and S15). Moreover, adagrasib, which exhibits a tighter contact to H95 than sotorasib, displays clear instability when in complex with NRAS and L95 is present in this location, as demonstrated by the increased distance to this residue (Figure ). Sotorasib maintains a consistent distance to the residue at position 95, regardless of the RAS isoform (Figure , 3E). Overall, our simulation results suggest that the interactions of adagrasib with H95 are deterministic for its KRAS(WT) binding and selectivity over other RAS(WT) isoforms. In contrast, sotorasib's interactions with H95 are not essential, allowing for higher tolerance for amino acid variations in this position.