Wednesday, 29 January 2014

Immunological 3D printing



Part 1: the pictures

As a good little geek, I’ve been itching to have a play with 3D printers for a while now. At first I’d mostly contemplated what bits and bobs I might produce for use in the lab, but then I started to see a number of fantastic 3D printed protein models.

Form is so important to function in biology, yet a lot of the time we biologists forget or ignore the shape and make-up of the molecules we study. As Richard Feynman one said, “it is very easy to answer many of these fundamental biological questions; you just look at the thing”.

3D printing protein structures represents a great opportunity to (literally) get to grips with proteins, cells, microbes and macromolecules. While I still recommend playing around with PDBs to get a feel for a molecule, having an actual physical, tactile item to hold appeals to me greatly.

So when I got access to the UCL Institute of Making, I got straight to work printing out examples of the immune molecules I study, T-cell receptors. You can read about how I made them here. Or, if you're just here for some pretty pictures of 3D prints, continue; here are the two I've printed so far.

Here are the two finished products! I apologise for the quality: a combination of my garish fluorescent office lighting and shonky camera-phones does not a happy photo make.
My first try: 3WPW. This is the A6 TCR, recognising the self-peptide HuD bound in the groove of the class I HLA-A2. HLA-A2 is coloured in dark pink, with β2 microglobulin in light pink, while the alpha and beta TCR chains are shown by light and dark blue respectively.
I particularly love the holes, crevices and caves pitted throughout the molecules. Having spent a goodly deal of time painstakingly pulling the scaffolding material out of these holes, I can confirm that you do indeed get a feel for the intricate surfaces of these structures.

You can imagine the antigen presenting cell on the left, with the T-cell on the right, as if we were watching from within the plane of the immunological synapse.

As a brief aside, in playing around with the 3PWP structure in PyMol (as detailed in an earlier blogpost) I was surprised to see the following; despite being a class I MHC (the binding grooves of which should be closed in at both ends) we can see the green of the peptide peeking out contributing to the surface mesh.

There's that HuD peptide!
The new addition: 3T0E. This brilliant ternary structure shows another autoimmune TCR, this time recognising a class II MHC, HLA-DR4, with an additional coreceptor interaction; enter CD4! Here we have the TCR chains coloured as above, while the HLA-DR alpha and beta chains are red and magenta respectively. Leaning in to touch the (membrane-proximal) foot of the MHC is the yellow CD4. Note that I took feedback, and this time went for a colour that didn't look so rice-puddingy.
The structure that became my second print was a particularly lucky find, as it contains not only a TCR-pMHC interaction, but also the CD4 coreceptor. This shot is angled as if we're inside the T-cell looking out across the synapse. If you imagine the various components of CD3 clustering around the constant region of the TCR you can really start to visualise the molecular complexity of even a single TCR-pMHC ligation event.

It's also quite nice to see that despite the differences in HLA composition between classes (one MHC-encoded chain plus B2M in class I versus two MHC-encoded chains in class II), they structurally seem quite similar by eye - at least at a surface level scale.

There you have it, my first forays into 3D printing immunological molecules. Let me know what you think, if you have any ideas for future prints - I'm thinking probably some immunoglobulins for the next run - or if you're going to do any printing yourself.

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