Faculty Collaboration Database

Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations. Biophys J 2026 Jan 20;125(2):485-501

Date

08/24/2025

Pubmed ID

40849684

Pubmed Central ID

PMC12680136

DOI

10.1016/j.bpj.2025.08.020

Scopus ID

2-s2.0-105015352668 (requires institutional sign-in at Scopus site)   1 Citation

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 Multiscale Machine-learned Modeling Infrastructure investigated different lipid compositions solely around the KRAS4b protein and the interplay between protein behavior and these membrane environments. Multiscale Machine-learned Modeling Infrastructure 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 multiresolution 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. Our studies suggest that orientations of the RAS-RBDCRD complex on the membrane occupy distinct configurational states, and the spatial patterns of lipid arrangements around these different protein states are unique to each state. The extent and size of lipid "fingerprints" imposed on the membrane by the RAS-RBDCRD protein complex are significantly larger than observed for just the RAS protein on its own. These protein complexes strongly associate, but we do not observe statistically significant preferred protein-protein orientations. These observations indicate that spatial colocalization of RAS-RBDCRD proteins in the same vicinity may be assisted by specific membrane environments, acting to increase the probability of signaling complex formation.

Author List

Carpenter TS, Aydin F, Neale C, Van QN, Zhang X, Bhatia H, Sidabras JW, Frank PH, Georgouli K, Tempkin JOB, Casamayor VB, Gulten G, Shrestha R, Goswami D, Di Natale F, Chavez JR, Moody A, Moon JY, Oppelstrup T, Glosli JN, Dharuman G, Wong S, Liu S, Hengartner NW, López CA, Nguyen K, Stanley CB, Stanton LG, Patel L, Reddy T, Turbyville TJ, Van Essen B, Bremer PT, Lightstone FC, Stephen AG, Gnanakaran S, McCormick F, Nissley DV, Streitz FH, Ingólfsson HI

Author

Jason W. Sidabras PhD, MS Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Membrane
Membrane Lipids
Molecular Dynamics Simulation
raf Kinases
ras Proteins