Chimera Multi-Scale Modeling Extension

Tom Goddard
October 18, 2002
Advisory Committee Talk

All images on this page ©2004 The Regents, University of California; all rights reserved.

Introduction

• For exploring models of large molecular complexes.
• Example systems are viruses and chromosomes.
• Goal is to provide capabilities in Chimera to explore systems where both large scale and atomic scale structure is important.
• NCRR research project - "Analyzing molecular complexes at multiple resolutions".
• Collaborating with Wah Chiu at Baylor College of Medicine on electron microscope studies of viruses.
• Collaborating with John Sedat at UCSF on electron and light microscope studies of chromosomes.
• Will show 4 example systems and demonstrate current Chimera capabilities.

Bluetongue Virus Core Particle

• PDB structure 2btv, 1998
• Picture shows ribbon diagram of one unit of icosahedral particle and surfaced representation of another unit.
• Making low resolution surfaces is done by multi-scale extension.
• Full particle 700 A diameter, 3.5 A resolution, 1000 crystals, 3 million atoms (no hydrogens)

Bluetongue Virus Architecture

• Multi-scale extension makes 60 copies of unit cell to show virus particle.
• Outer layer has 260 trimers of VP7 protein in 5 symmetry classes.
• Inner layer has 60 dimers of VP3.
• Computer view of virus architecture shown in diagram.
• Not all of this architecture is in computer readable form from PDB entry.
• To hide outer layer computer must know what "outer layer" is.
• Multi-scale extension focuses on encoding and using this hierarchical structure information.

Why Look at Full Virus?

• Image shows viral dsRNA attached to outside of virus particle.
• Thought to be a means to sequester excess viral RNA to avoid cell shutdown.
• Atomic scale and large scale useful for studying stickiness of shell and RNA.
• 60% of RNA / trimer contacts are with 5 polar residues.
• Work published by David Stuart's group at Oxford, September 2002.

Demonstration Showing Bluetongue Virus in Chimera

• Show selection of outer monomer with mouse.
• Show selection promotion to trimer and trimer class.
• Show hiding trimers around 5 fold axis.
• Hide outer layer.
• Show all except half of outer layer.
• Show inner layer monomer as ribbon.
• Show other inner layer monomer as ball and stick colored by element.
• Use near and far slice planes to show thinness of inner layer.

Current Multi-Scale Capabilities

• Creates low resolution surface depictions.
• Creates multimeric complexes from monomers.
• Understands higher order structure.
• Allows both atomic and surface display styles.
• Details:
  • Models made automatically from PDB chains and matrix transformations.
  • More control specifying higher levels of structure using Python script.
  • Select chains with mouse and promote selections.
  • Selections control what is displayed, display style (surface, ribbon, ...), and colors.
  • Adjustable level of detail effects all surfaces.

Rice Dwarf Virus Electron Microscope Density Map

• Rice dwarf virus is in the same family as Bluetongue virus (reoviridae).
• Core particle has 2 layer shell and dsRNA genome.
• Crystal structures of shell proteins have not been determined.
• Density map from electron cryo-microscopy of 3261 full virus particles from Wah Chiu's lab.
• Density map is hand segmented into layers, trimers, dimers and monomers.
• Averaging outer layer P8 monomer EM density gives 7 A resolution.
• Secondary structure (alpha helices and beta sheets) visible.
• Pictures: full particle, inner layer dimer, shell and dsRNA strata, outer layer trimer, outer layer monomer.

Heterogeneous Data in Multi-Scale Models

• Multi-scale model can consist of components that are segmented regions of EM density map.
• Modeled backbone trace can also be a component.
• Structure components can contain atomic models, X-ray density maps, EM density maps, secondary structure tracings, theoretical models (eg. dsRNA genome packing).
• A multi-scale model component can contain more than one type of data.

Virus Images from Other Software

• Journal images of viruses commonly done in GRASP, MolScript, IRIS Explorer, Raster3D, ....
• These systems provide beautiful high resolution publication images.
• Radially colored density maps of viruses are common.
• The graphics are typically molecular surfaces that render too slowly for use in interactive analysis.
• These programs do not understand the different structural levels of large complexes which limits their usefulness for interactive analysis.

Chromatin 30 nm Fiber

• DNA in eukaryotes is usually packaged as a 30 nm fiber called chromatin.
• Fiber is composed of nucleosomes and accessory proteins.
• Nucleosomes consist of a histone protein octamer wrapped with ~2 turns of DNA, about 200 base pairs.
• Nucleosome crystal structure is shown.
• Conceptual model of fiber with 100 nucleosomes is shown. Detailed structure is unknown.
• Histone tails thought to hold chromatin together.

Displaying Less Detail

• Showing nucleosomes as pellets provides clearer view of chromatin model than more detailed rendering.
• User specified geometric representations could be supported.
• A single user specified triangle could represent a virus shell trimer.
• Need control over which level of structure hierarchy gets surfaced.
• Surface resolution needs to be adjustable to not overwhelm graphics hardware.

Large Ribosomal Subunit

• PDB model 1jj2, 30 different chains, 90000 atoms (no hydrogens).
• Non-multimeric complex.
• There are 8 large ribosomal subunit structures and several other partial structures in PDB.
• Different structures have bound anti-biotics, or protein synthesis intermediates, or are from different species.
• Low-resolution display capability can be useful to compare these large complexes.

Future Multi-Scale Improvements

• Optimization. Currently 10 times slower surfacing than necessary.
• User interface to specify model hierarchy.
• File format to save model hierarchy.
• Handle EM or X-ray density maps or secondary structure models (currently only molecular chains).
• Surface representation for model components above chain level.
• Surface level of detail for individual components.
• Naming of different levels of model ("outer layer", "VP7 trimer", ...).
• User specified representations (cylinders, individual triangles).
• Write documentation.
• Interact with leading edge users to guide development.
• Distribute with Chimera.