Understanding the influence of AMG 510 on the structure of KRAS empowered by molecular dynamics simulation.

The KRAS mutant is often associated with human cancers, and AMG 510 as a promising covalent inhibitor of KRAS has achieved surprising efficacy in clinical trials. However, the interaction mechanism between KRAS and AMG 510 is not completely understood. Here, we performed all-atom molecular dynamics simulations on the complex of KRAS-AMG 510 to explore the influence of this covalent inhibitor on the conformational change of KRAS. A PCA (Principal Component Analysis) model was constructed based on known KRAS crystal structures to distinguish different conformations (active, inactive, and other). By mapping simulation trajectories onto the PCA model, we observed that the conformations of KRAS bound with AMG 510 were mainly concentrated in the inactive conformation. Further analysis demonstrated that AMG 510 reduced the flexibility of two switch regions to make the complex of KRAS-AMG 510 restricted in the inactive conformation. In the meantime, we also identified key interacting residues between KRAS and AMG 510 through the calculation of binding energy. Finally, we built a series of KRAS second-site mutation systems (i.e. KRAS) to conduct large-scale screening of potential resistance mutations. By further combining MD simulations and the PCA model, we not only recapitulated the currently known resistance mutations of AMG 510 successfully but also proposed some novel potential resistant mutations. Taken together, these results broaden our insight into the influence of AMG 510 on the conformational change of the KRAS mutant at the atomic level, thereby providing crucial hints for the improvement and optimization of drug candidates.