Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

Journal: Proceedings of the National Academy of Sciences of the United States of America
PMID: 34983849

Abstract

RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

Authors

  • Helgi I Ingólfsson
    Biochemical and Biophysical Systems Group, Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California, United States.
  • Chris Neale
    Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Timothy S Carpenter
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Rebika Shrestha
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Cesar A Löpez
  • Timothy H Tran
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Tomas Oppelstrup
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Harsh Bhatia
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Liam G Stanton
    Department of Mathematics and Statistics, San José State University, San José, CA 95192.
  • Xiaohua Zhang
    Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China.
  • Shiv Sundram
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Francesco Di Natale
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Animesh Agarwal
    Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Gautham Dharuman
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Sara I L Kokkila Schumacher
    Data Centric Systems, IBM T. J. Watson Research Center, Yorktown Heights, NY 10598.
  • Thomas Turbyville
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Gulcin Gulten
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Que N Van
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Debanjan Goswami
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Frantz Jean-Francois
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Constance Agamasu
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • De Chen
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Jeevapani J Hettige
    Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Timothy Travers
    Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Sumantra Sarkar
    Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Michael P Surh
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Yue Yang
    Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.
  • Adam Moody
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Shusen Liu
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Brian C Van Essen
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Arthur F Voter
    Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Arvind Ramanathan
    Biomedical Sciences, Engineering, and Computing Group, Health Data Science Institute, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
  • Nicolas W Hengartner
    Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • Dhirendra K Simanshu
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Andrew G Stephen
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701.
  • Peer-Timo Bremer
    Computing Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • S Gnanakaran
  • James N Glosli
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550.
  • Felice C Lightstone
    Biochemical and Biophysical Systems Group, Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550, United States.
  • Frank McCormick
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701; frank.mccormick@ucsf.edu nissleyd@mail.nih.gov streitz1@llnl.gov.
  • Dwight V Nissley
    RAS Initiative, The Cancer Research Technology Program, Frederick National Laboratory, Frederick, MD 21701; frank.mccormick@ucsf.edu nissleyd@mail.nih.gov streitz1@llnl.gov.
  • Frederick H Streitz
    Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550; frank.mccormick@ucsf.edu nissleyd@mail.nih.gov streitz1@llnl.gov.

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