Science Forum: Nanoscape, a data-driven 3D real-time interactive virtual cell environment

  1. Shereen R Kadir
  2. Andrew Lilja
  3. Nick Gunn
  4. Campbell Strong
  5. Rowan T Hughes
  6. Benjamin J Bailey
  7. James Rae
  8. Robert G Parton
  9. John McGhee  Is a corresponding author
  1. 3D Visualisation Aesthetics Lab, School of Art and Design, and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Australia
  2. Institute for Molecular Bioscience, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and Centre for Microscopy and Microanalysis, University of Queensland, Australia
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17 figures, 11 videos, 1 table and 1 additional file

Figures

Relative scales and temporal dynamics of the cell surface components featured in Nanoscape.

A 3D model of a breast cancer cell (upper left panel). The region inside the yellow box is shown in more detail in the lower left panel, and region inside the pink box is shown in more detail in the …

3D modelled cell surface receptors and ligands featured in Nanoscape.

Stylized 3D meshes modelled from structures retrieved from the RSCB Protein Data Bank (PDB). Most proteins are depicted as monomers; see Appendix 1 for details.

Representations of surface receptors and plasma membrane lipids.

(A) Structural and dynamic information about the four proteins in the ErbB family of proteins (EGFR, Her2, Her3, and Her4) and their ligands. Top: Mechanism of action for EFGR which, upon ligand …

Cell surface receptor density modelling from experimental data.

(A) PDB meshes of 6 well-known surface biomarkers (CD44, EGFR, EpCAM, Her2, ICAM1 and αVβ3 integrin) on MDA-MB-231 cells from flow cytometry data (Cahall et al., 2015). (B) Scaled receptor meshes …

Scanning electron microscope (SEM) and transmission electron microscope (TEM) images of MDA-MB-231 cells showing cellular features used in Nanoscape.

(A) Representative SEM images of MDA-MB-231 cells. The boxed area shows a higher magnification of filopodia (pseudocoloured blue) and putative pits (caveolae, clathrin coated pits) in red. (B) …

A 3D artistic impression of the extracellular matrix in a tumour microenvironment.

A pre-production sketch (A) and a 3D model (B) of collagen I fibrillar bundles and proteoglycans (such as hyaluronic acid). (C) Collagen IV protomers and dimers. (D) Fibronectin dimers bound to …

Models of components in the tumour microenvironment.

(A) Additional neighbouring cancer cells (transparent) surrounding the central or main cancer cell. (B) Cancer-associated fibroblasts (CAFs) entangled in collagen fibres. (C) Leaky blood vessel …

Nanoscape real-time open-world experience.

Vistas from the Nanoscape real-time open-world experience with key cellular features and microenvironment components highlighted. (A–C) Panoramic views showing surface receptors on the plasma …

Appendix 2—figure 1
Two members of the ErbB family of surface receptors.

(A) Inactive (left) and active (right) EGFR. (B) Inactive Her3 (left) and active Her4 (right).

Appendix 3—figure 1
The three major conformational states of integrin.

(A) Bent with closed headpiece; (B) extended with a closed headpiece; (C) extended with an open headpiece. Extracellular domains in alpha chains (lower left) and beta chains (lower right).

Appendix 4—figure 1
Two views of the VEGFR1–VEGF-A composite dimer.
Appendix 5—figure 1
A c-KIT monomer (left) and a c-KIT homodimer (right) after binding by a Stem Cell Factor (SCF) protomer.
Appendix 6—figure 1
The inactive insulin receptor dimer has an inverted U shape (upper panel).

The active insulin receptor dimer has a T shape (lower panel); the insulin ligand is shown in green.

Appendix 7—figure 1
The structure of Tetraspanin CD81.
Appendix 8—figure 1
Different views of the DcR3-FASL complex, which consists of a trimeric ligand (green) bound to three upright decoy receptors (orange/purple).
Appendix 8—figure 2
Top and side views of a TNFSF protein complex featuring DR5 ligand (purple), TRAIL (blue) and antibody Fab fragments (orange/yellow).
Appendix 9—figure 1
Different views of the GLUT1 surface receptor, including its outward-open and inward-open states.

Videos

Video 1
Animated models of five cellular processes – macropinocytosis (upper right), caveolae (middle left), clathrin coated pits (middle right), exosomes (lower left) and filopodia (bottom lower) – created in Maya.

The human figure shown in some of the models is 40 nm tall. Figure 1 and Figure 5 provide more information about these processes.

Video 2
Animation showing red blood cells flowing through a leaky blood vessel surrounded by basement membrane mesh in the Nanoscape tumour microenvironment (see also Figure 7).
Appendix 2—video 1
Animation strategy for EGFR.

1NQL = inactive EGFR (monomer; Ferguson et al., 2003). 3NJP = active EGFR (dimer; Lu et al., 2010). Rigged 1NQL with mMaya rigging kit, created elastic networks for each domain: I + II combined, …

Appendix 2—video 2
Animation strategy for Her3.

1M6B = inactive Her3 (monomer; Cho, 2002). 3U7U = active Her4 (dimer; Liu et al., 2012). Rigged 1M6B with mMaya rigging kit, created elastic networks for each domain: I + II combined, III, and IV. …

Appendix 3—video 1
Animation strategy for αVβ3 integrin.

4G1M = αVβ3 inactive bent conformation (Dong et al., 2012). 2K9J = transmembrane domain of integrin αIIb-β3 (Lau et al., 2009). Connected 2K9J to the C-term of αVβ3 integrin (4G1M) using the mMaya …

Appendix 4—video 1
Animation strategy for VEGFR1.

The composite VEGFR1 dimer was built from 5T89 and 3KVQ (see Appendix 4—figure 1) and rigged using mMaya rigging kit. Elastic networks were created for each domain (D1 to D7). Handles were made for …

Appendix 5—video 1
Animation strategy for c-KIT.

2EC8 = c KIT monomer (Yuzawa et al., 2007). 2E9W = c KIT homodimer with SCF (Yuzawa et al., 2007). Aligned chain A from 2E9W (dimer conformation) to 2EC8 (monomer conformation). Saved a new PDB …

Appendix 6—video 1
Animation strategy for the insulin receptor.

4ZXB = inactive model (– ligands; Croll et al., 2016). 6CEB = active model (+ligands; Scapin et al., 2018). The missing FnIII-3 domain in 6CEB chain A was added using the mMaya modelling kit to get …

Appendix 7—video 1
Animation strategy for Tetraspanin.

5TCX = Tetraspanin (closed conformation (i.e. cholesterol-bound); Zimmerman et al., 2016). Rigged 5TCX, created elastic networks for EC2 (residues 34–55 and 113–201), TM1 (6–33), TM2 (56–84), TM3 …

Appendix 8—video 1
Animation strategy for TNFR1.

4MSV = Decoy receptor 3 (DcR3)(chain A) and FasL (chain B; Liu et al., 2016). 2NA7 = Transmembrane domain of human Fas/CD95 death receptor (Fu et al., 2016). 4N90 = Crystal structure of TRAIL-DR5 …

Appendix 9—video 1
Animation strategy for GLUT1.

4PYP = GLUT1; inward-open state (Deng et al., 2015). 4ZWC = GLUT3; outward-open state (Deng et al., 2014). Rigged 4PYP (chain A) (inward-open state) was targeted to conformationally morph …

Tables

Table 1
Cellular structures and processes in Nanoscape.
FeatureExamplesDimensionsDensityTemporal dynamics
StructuresMembrane bound receptors1EGFR, Integrins, VEGFR~5–20 nm length;
~1–5 nm diameter
Protein specific
~10–104 per µm2
Protein specific
D ~ 10−3–1 µm2/s [see note 10];
Transitions between protein states ~ 1–100µs
Soluble proteins1EGF, TNF, MMPs
Membrane transport proteins2GLUT4, K+ channel, Na+/K+ pump~4–10 nm length~104 per µm2~100–107/s transport rate
Extracellular matrix3Collagens, Fibronectin, Hyaluronic acidVariable: from large fibres to smaller glycoproteinsVariableVery low mobility relative to proteins
Plasma membrane4Phospholipids~2 nm length;~0.25–0.5 nm2 cross-sectional area~5×106 per µm2D ~ 1 µm2/s
ProcessesProtrusionsFilopodia5~1–5 µm length;
~150–200 nm diameter
~0.3 per µm2~25–50 nm/s protrusion rate
EndocytosisCaveolae6~65 nm mean diameter;
~0.0067 µm2 area
~10 per µm2~30 s to minutes
Clathrin mediated endocytosis7~110 nm mean diameter;
~0.0190 µm2 area
~0.8 per µm2~30–60 s
Macropinocytosis8~0.2–5 µm diameter?~120 s
Extracellular vesiclesExosomes9~40–150 nm diameter??
  1. * Key features of cellular structures and processes in Nanoscape, with examples detailing properties such as dimensions, densities, temporal dynamics. See Figure 1 for 3D models.

    Notes: 1 Membrane bound receptors and soluble proteins. Milo et al., 2010. 2 Membrane transport proteins. Milo et al., 2010. Chapter IV in Milo and Phillips, 2015. Page 9 (top paragraph) in Itzhak et al., 2016. Table 8.3 in Gennis, 1989. 3 Extracellular matrix. Frantz et al., 2010. Insua-Rodríguez and Oskarsson, 2016; Früh et al., 2015; Mouw et al., 2014; Pankov and Yamada, 2002. 4 Plasma membrane lipids. Milo et al., 2010. Chapter II in Milo and Phillips, 2015. Chapter 10 in Alberts et al., 2002. Table 1 in Rawicz et al., 2000. Page 2644 (right column, 2nd paragraph) in Brügger et al., 2006. 5 Filopodia density and dimensions. Measured from scanning electron micrographs, see Figure 5 in Mallavarapu and Mitchison, 1999. 6 Caveolae density, dimensions and temporal dynamics. Parton, 1994; Parton et al., 2020a; Parton et al., 2020b; Pelkmans and Zerial, 2005; Boucrot et al., 2011; Richter et al., 2008. 7 Clathrin mediated endocytosis density, dimensions and temporal dynamics. Cocucci et al., 2012; Doherty and McMahon, 2009; Edeling et al., 2006; Kirchhausen, 2009; McMahon and Boucrot, 2011; Merrifield et al., 2002; Parton, 1994; Saffarian and Kirchhausen, 2008; Taylor et al., 2011. 8 Macropinocytosis dimensions. Condon et al., 2018; Lim and Gleeson, 2011. 9 Exosome dimensions. Skotland et al., 2017. 10 Diffusion coefficient. D is microscopically determined by the velocity of the molecule and the mean time between collisions.

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