Skip to main content

Accurately predict the spatial arrangement of protein complexes from subtomogram images through physics-informed machine learning


EMSL Project ID
60121

Abstract

Deducing three-dimensional (3D) structures of molecular assemblies from cryo-electron tomography (cryoET) data provides an unprecedented level of detail about biological systems in their native unperturbed state. The proposed work is focused on the automation of subtomogram averaging (SA) - a reconstruction approach that extracts a 3D structure of the specimen from series of 3D sub-volumes that individually show different and incomplete views of the same structure. SA currently constitutes an arduous process requiring manual intervention to identify and box out all the sub-volumes of interest. One of the main challenges to fully automate SA is the number of tomogram sub-volumes (>10,000) to achieve even 6Å resolution. Due to this, most examples of SA to date have looked at complexes at high copy number in cells and machines with low variations in compositions and dynamics. However, interesting protein complexes that form dynamic clusters often appear as particles with low density in electron tomograms and are often filtered out as noise in a reconstructed voxel during a standard ensemble averaging technique. The main technical objective of this work is to leverage the structural ensemble of protein conformations from molecular dynamics simulations as physical constraints for machine learning. This will be complimented by developing a reproducible, well-defined, and automated pipeline for SA which will significantly increase the throughput of SA data processing and lessen the number of required input datasets.

Project Details

Start Date
2021-11-16
End Date
2023-10-31
Status
Closed

Team

Principal Investigator

Margaret Cheung-Wyker
Institution
Environmental Molecular Sciences Laboratory

Team Members

Malio Nelson
Institution
University of Washington

Katharine Baldwin
Institution
Environmental Molecular Sciences Laboratory

Arsam Firoozfar
Institution
Environmental Molecular Sciences Laboratory

Jesse Fichman
Institution
Environmental Molecular Sciences Laboratory

Eve Johnson
Institution
University of Washington

Christopher Cotillo
Institution
Pacific Northwest National Laboratory

Liam Mackey
Institution
Environmental Molecular Sciences Laboratory

Yasmene Elhady
Institution
University of Washington

Jose Vega-Villalobos
Institution
Environmental Molecular Sciences Laboratory

Ian Gildea
Institution
Environmental Molecular Sciences Laboratory

Chengxuan Li
Institution
University of Washington

Jules Nde
Institution
University of Washington

August George
Institution
Environmental Molecular Sciences Laboratory

Doo Nam Kim
Institution
Pacific Northwest National Laboratory

Hoshin Kim
Institution
Pacific Northwest National Laboratory

Trevor Moser
Institution
Environmental Molecular Sciences Laboratory

James Evans
Institution
Environmental Molecular Sciences Laboratory

Evan Felix
Institution
Environmental Molecular Sciences Laboratory

Marat Valiev
Institution
Environmental Molecular Sciences Laboratory