Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations

Abstract

To gain molecular and mechanistic insights into initiation of the RAS-RAF signaling cascade we developed and used a combination of multiscale simulation and experimental approaches. The influence and impact of the membrane on RAS and RAF proteins is a factor we are just beginning to understand and appreciate in more detail. Molecular simulation is an ideal methodology to further study this complicated relationship between the membrane and associated proteins. Our previous work using MuMMI (Multiscale Machine-learned Modeling Infrastructure) investigated different lipid compositions solely around the KRAS4b protein and the interplay between protein behavior and these membrane environments. MuMMI uses machine learning to couple adjacent simulation scales and has been efficiently scaled across some of the world’s largest high-performance computers. Recently, we have expanded this multi-resolution framework to include the all-atom simulation scale, and to incorporate the RAF RBDCRD domains. Here we present the overall analysis results from this new simulation campaign comprising a mixture of RAS and RAF RBDCRD proteins. Approximately 35,000 coarse-grained, and 10,000 all-atom molecular dynamics simulations were completed, sampled from a variety of protein/lipid composition configurations that were generated from a micron-scale continuum simulation containing hundreds of copies of the proteins.