Publication Date

5-9-2023

Document Type

Article

Publication Title

Journal of Chemical Theory and Computation

Volume

19

Issue

9

DOI

10.1021/acs.jctc.2c01018

First Page

2658

Last Page

2675

Abstract

Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence is especially true for a well-known cancer signaling pathway, where the membrane-bound RAS protein binds an effector protein called RAF. To capture the driving forces that bring RAS and RAF (represented as two domains, RBD and CRD) together on the plasma membrane, simulations with the ability to calculate atomic detail while having long time and large length- scales are needed. The Multiscale Machine-Learned Modeling Infrastructure (MuMMI) is able to resolve RAS/RAF protein-membrane interactions that identify specific lipid-protein fingerprints that enhance protein orientations viable for effector binding. MuMMI is a fully automated, ensemble-based multiscale approach connecting three resolution scales: (1) the coarsest scale is a continuum model able to simulate milliseconds of time for a 1 μm2 membrane, (2) the middle scale is a coarse-grained (CG) Martini bead model to explore protein-lipid interactions, and (3) the finest scale is an all-atom (AA) model capturing specific interactions between lipids and proteins. MuMMI dynamically couples adjacent scales in a pairwise manner using machine learning (ML). The dynamic coupling allows for better sampling of the refined scale from the adjacent coarse scale (forward) and on-the-fly feedback to improve the fidelity of the coarser scale from the adjacent refined scale (backward). MuMMI operates efficiently at any scale, from a few compute nodes to the largest supercomputers in the world, and is generalizable to simulate different systems. As computing resources continue to increase and multiscale methods continue to advance, fully automated multiscale simulations (like MuMMI) will be commonly used to address complex science questions.

Funding Number

DE-AC52-06NA25396

Funding Sponsor

National Institutes of Health

Comments

Full author list: Helgi I. Ingólfsson, Harsh Bhatia, Fikret Aydin, Tomas Oppelstrup, Cesar A. López, Liam G. Stanton, Timothy S. Carpenter, Sergio Wong, Francesco Di Natale, Xiaohua Zhang, Joseph Y. Moon, Christopher B. Stanley, Joseph R. Chavez, Kien Nguyen, Gautham Dharuman, Violetta Burns, Rebika Shrestha, Debanjan Goswami, Gulcin Gulten, Que N. Van, Arvind Ramanathan, Brian Van Essen, Nicolas W. Hengartner, Andrew G. Stephen, Thomas Turbyville, Peer-Timo Bremer, S. Gnanakaran, James N. Glosli, Felice C. Lightstone, Dwight V. Nissley, and Frederick H. Streitz

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Department

Mathematics and Statistics

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