Extended Data Fig. 10. Molecular dynamics simulations of SHOC2:PP1C:RAS interactions with peptides.

a, Principal component analysis (PCA) of each peptide:protein simulation showing clusters of stable states within each simulation. Representative structures were chosen from within the most populated states, as indicated (black lines). Representative structures were aligned based on the final LRR and C-terminal capping helices of SHOC2 to place the SHOC2 hydrophobic groove on a common view. Only a single SHOC2:PP1C:MRAS complex is shown for clarity. RAF NTpS peptides interact with the SHOC2 hydrophobic groove in a majority of simulations, but not for the Non-Target Peptides. Hydrophobic interactions likely consist of a considerable entropic portion, preventing accurate calculations for free energy of binding for these models. b, Model of RAS binding. Under normal conditions, H/K/NRAS is the preferred binding partner of RAF, whilst MRAS is preferred for SHOC2:PP1C. RAF and SHOC2:PP1C:RAS co-localize at the membrane prior to substrate dephosphorylation.