KRAS(G12C)-AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations

Area of Science:

• Oncology
• Molecular Biology
• Computational Chemistry

Background:

• AMG 510 is the first KRAS G12C inhibitor in clinical trials with promising antitumor activity.
• The precise molecular interaction dynamics of the KRAS G12C-AMG 510 complex remain undetermined.

Purpose of the Study:

• To elucidate the interaction dynamics of the KRAS G12C-AMG 510 complex using long timescale molecular dynamics simulations.
• To investigate the impact of KRAS N-terminal post-translational modification (PTM) on these dynamics.

Main Methods:

• All-atom molecular dynamics (MD) simulations totaling 75 μs.
• Analysis of KRAS G12C-AMG 510 complex dynamics and the influence of N-terminal PTM.

Main Results:

• AMG 510 induces an ensemble of KRAS conformations, not a single trapped state.
• AMG 510 binding is highly stable despite the dynamic nature of the KRAS interface.
• The complex partially mimics native GDP-bound KRAS dynamics, with AMG 510 stabilizing the α3-helix.
• N-terminal modified KRAS shows similar interaction dynamics, with the PTM stabilizing the β2-β3 loop.

Conclusions:

• Novel conformational insights into KRAS G12C-AMG 510 interactions and dynamics.
• Provides a molecular-level understanding that can inform future RAS-targeted drug discovery efforts.