KRAS(G12C)\u2013AMG\xa0510 interaction dynamics revealed by all-atom molecular dynamics simulations

Tatu Pantsar

doi:10.1038/s41598-020-68950-y

Abstract

The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug–protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)–AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS’ N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS’ switches. Overall, KRAS(G12C)–AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2–β3-loop. These results provide novel conformational insights on the molecular level to KRAS(G12C)–AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery.

Highlights

The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials
G12C is a suitable target for pharmacological intervention via a covalent inhibition of a small molecule drug[7], providing a potential strategy to target this oncogenic KRAS mutant protein
We investigated for the first-time the effect of the N-terminal post-translational modification (PTM) on KRAS dynamics by molecular dynamics (MD) simulations

Summary

Introduction

The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met[1] is present, but this PTM appears to stabilize β2–β3-loop These results provide novel conformational insights on the molecular level to KRAS(G12C)–AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery. The first covalent drug in the clinical development, AMG 510 (Fig. 1A), demonstrated promising antitumor a ctivity[12]. Another G12C targeting inhibitor, for which clinical data has been reported, is MRTX849 from Mirati Therapeutics[13]. From the covalent inhibitors in the clinical development, AMG 510 in complex with KRAS was the first structure that was made publicly available (Fig. 1B) (PDB ID: 6oim)[12]. The KRAS(G12C)–AMG 510 complex is a high-resolution structure (1.65 Å)

Methods

Results

Conclusion