Publication Date
8-22-2025
Document Type
Article
Publication Title
Biophysical Journal
DOI
10.1016/j.bpj.2025.08.020
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.
Funding Number
75N91019D00024
Funding Sponsor
U.S. Department of Energy
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Department
Mathematics and Statistics
Recommended Citation
Carpenter, T. S., Aydin, F., Neale, C., Van, Q. N., Zhang, X., Bhatia, H., Sidabras, J. W., Frank, P. H., Georgouli, K., Tempkin, J. O., Casamayor, V. B., Gulten, G., Shrestha, R., Goswami, D., Di Natale, F., Chavez, J. R., Moody, A., Moon, J. Y., Oppelstrup, T., . . . Ingólfsson, H. I. (2025). Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations. Biophysical Journal. https://doi.org/10.1016/j.bpj.2025.08.020
Comments
Full authors list:
Timothy S. Carpenter, Fikret Aydin, Chris Neale, Que N. Van, Xiaohua Zhang, Harsh Bhatia, Jason W. Sidabras, Peter H. Frank, Konstantia Georgouli, Jeremy O.B. Tempkin, Violeta Burns Casamayor, Gulcin Gulten, Rebika Shrestha, Debanjan Goswami, Francesco Di Natale, Joseph R. Chavez, Adam Moody, Joseph Y. Moon, Tomas Oppelstrup, James N. Glosli, Gautham Dharuman, Sergio Wong, Shusen Liu, Nicolas W. Hengartner, Cesar A. López, Kien Nguyen , Christopher B. Stanley, Liam G. Stanton, Lara Patel, Tyler Reddy, Thomas J. Turbyville, Brian Van Essen, Peer-Timo Bremer, Felice C. Lightstone, Andrew G. Stephen, Sandrasegaram Gnanakaran, Frank McCormick, Dwight V. Nissley, Frederick H. Streitz, Helgi I. Ingólfsson