6 ms·

Design of a hyperstable 60-subunit protein icosahedron

42 points by te_platt 10y ago

imdsm 10y ago
Could someone ELI-human? Ta
- stephengillie 10y ago
  They made a really big, really stable molecule, inside an E Coli bacterium.
  - toufka 10y ago
    That is producible in huge quantities on demand (for the cost of sugar, sunlight and water). That is defined with atomic specificity. And can have appendages and payloads of arbitrary (genetic) sequence attached to it (again with atomic specificity).
    - lohankin 10y ago
      "... attached to it with atomic specificity" - and then what?
      - pazimzadeh 10y ago
        Enzymes and substrates could be grouped together so that they work more efficiently (don't have to bump around looking for each other in a large space). Synthetic machinery that we design could be made functional inside the protein complex so as not to disturb background cellular processes. Receptors for specific cell types could be attached to the outside so that the complex is taken up and a payload is delivered.
    - Eerie 10y ago
      >That is defined with atomic specificity. All gene-encoded proteins are defined with atomic specificity. Well, atomic specificity as long as you ignore the existence of stable nuclear isotopes.
pierrec 10y ago
Ouch, that comment: Those are not icosahedra; they're dodecahedra. A regular icosahedron has 20 faces and 12 vertices. No matter how I look at it, it seems to be right. I wonder if they have a good reason for abusing nomenclature like that. Or perhaps they'll have to issue a rather embarrassing errata stating the very title was wrong. And an unrelated but equally bewildering thing: the page has this "editor's pick" section containing a uselessly gigantic 5672x1823px image resized to 280x90px. What the fuck.
- deleted 10y ago
  [deleted]
- dekhn 10y ago
  I'm guessing here, but it's probably because dodecahedra have icosahedral symmetry (https://en.wikipedia.org/wiki/Icosahedral_symmetry https://en.wikipedia.org/wiki/Icosahedral_symmetry) and dodecahedrons are the dual of icosahedrons (see the row equating them here: https://en.wikipedia.org/wiki/Capsid#Triangulation_number https://en.wikipedia.org/wiki/Capsid#Triangulation_number) Realistically it's most likely that Baker is using the terminology from crystallography and virus studies, consistent with his background.
davi 10y ago
Hey cool, 3rd author Shane Gonin is now at Janelia (where my lab is) and I know a bit about this work. Funny to see it pop up here. The kind of electron microscopy (EM) of brain tissue I do relies upon embedding the tissue in a resin called Epon. Epon has excellent cutting properties and low intrinsic contrast in EM. But in order to embed tissue in Epon it has to be completely dehydrated, which quenches genetically expressed fluorphores like GFP. My fantasy for these genetically expressed buckyball-like proteins is that one could engineer their interior to be sufficiently hydrophilic that GFP fluorescence would survive complete dehydration of the surrounding tissue, instead relying on the polarized residues of the amino acids in the interior. This would let us combine highest quality EM with highest quality light microscopy in the same sample -- which would be very useful indeed.
- dekhn 10y ago
  I doubt you could avoid diffusion in these proteins to the point you desire. It would be worth looking into species that exploit cryptobiosis, specifically anhydrobiosis (rotifers, tardigrades, daphnia, and C. Elegans are all examples). In most cases they can dessicate extremely, some of them by exchanging glucose or water with trehalose (itself a fascinating topic worth further study), so i wonder if you could make trehalose binding sites inside the body.
lrc 10y ago
Reminds me of the Andromeda Strain (except that didn't have any amino acids) http://mymeaningfulmovies.blogspot.com/2015/02/the-andromeda-strain.html http://mymeaningfulmovies.blogspot.com/2015/02/the-andromeda...
derogator 10y ago
For anyone paying attention, the dearth of comments in this thread is a key indicator that the most commented threads on HN are all bike shedding threads. A topic like this suffers from high barriers that prevent the formation of opinions, whereas today's Pardon Snowden thread[0] provides ample opportunity for lengthy editorials. [0] https://news.ycombinator.com/item?id=12494998 https://news.ycombinator.com/item?id=12494998
OrthoMetaPara 10y ago
The fact that you can tack on an extra protein domain to each protein subunit is really neat because it lets you assemble little macromolecules containing several custom functionalities. Presumably these extra domains face outwards, coating the surface of the cage. Hopefully these extra domains don't interfere with the cage assembly process. For example, say you created fusions between the cage mononmer and antibody Fv chains that bind two different proteins (A and B) and then you created fusions between the cage monomer and two different fluorescent proteins (GFP and RFP). In bacteria strain 1, you express fusion A and fusion GFP so that you assemble cages that will show a green signal where-ever A is found (e.g., for fluorescent microscopy). Likewise, in bacterial strain 2, you expression fusions B and RFP so that you get a red signal where ever B is. You could use these as detectors in a western blot, for example. (Obviously there are better, established ways to detect proteins of interest in a western blot, but that's just a simple idea). Another idea that I remember reading about was creating glucuronidase fusions to antibody fragments designed to bind cancer cells. The patient would then be administered the glucuronide of a cytotoxic drug, which is not toxic in its glucuronide form. The idea is that the antibody fusion protein would activate the drug so that it would be concentrated highly near the cancer cell and nowhere else.

42 points by te_platt 10y ago

imdsm 10y ago

Could someone ELI-human? Ta

stephengillie 10y ago
They made a really big, really stable molecule, inside an E Coli bacterium.
- toufka 10y ago
  That is producible in huge quantities on demand (for the cost of sugar, sunlight and water). That is defined with atomic specificity. And can have appendages and payloads of arbitrary (genetic) sequence attached to it (again with atomic specificity).
  - lohankin 10y ago
    "... attached to it with atomic specificity" - and then what?
    - pazimzadeh 10y ago
      Enzymes and substrates could be grouped together so that they work more efficiently (don't have to bump around looking for each other in a large space). Synthetic machinery that we design could be made functional inside the protein complex so as not to disturb background cellular processes. Receptors for specific cell types could be attached to the outside so that the complex is taken up and a payload is delivered.
  - Eerie 10y ago
    >That is defined with atomic specificity. All gene-encoded proteins are defined with atomic specificity. Well, atomic specificity as long as you ignore the existence of stable nuclear isotopes.

pierrec 10y ago

Ouch, that comment: Those are not icosahedra; they're dodecahedra. A regular icosahedron has 20 faces and 12 vertices. No matter how I look at it, it seems to be right. I wonder if they have a good reason for abusing nomenclature like that. Or perhaps they'll have to issue a rather embarrassing errata stating the very title was wrong. And an unrelated but equally bewildering thing: the page has this "editor's pick" section containing a uselessly gigantic 5672x1823px image resized to 280x90px. What the fuck.

deleted 10y ago
[deleted]
dekhn 10y ago
I'm guessing here, but it's probably because dodecahedra have icosahedral symmetry (https://en.wikipedia.org/wiki/Icosahedral_symmetry https://en.wikipedia.org/wiki/Icosahedral_symmetry) and dodecahedrons are the dual of icosahedrons (see the row equating them here: https://en.wikipedia.org/wiki/Capsid#Triangulation_number https://en.wikipedia.org/wiki/Capsid#Triangulation_number) Realistically it's most likely that Baker is using the terminology from crystallography and virus studies, consistent with his background.

davi 10y ago

Hey cool, 3rd author Shane Gonin is now at Janelia (where my lab is) and I know a bit about this work. Funny to see it pop up here. The kind of electron microscopy (EM) of brain tissue I do relies upon embedding the tissue in a resin called Epon. Epon has excellent cutting properties and low intrinsic contrast in EM. But in order to embed tissue in Epon it has to be completely dehydrated, which quenches genetically expressed fluorphores like GFP. My fantasy for these genetically expressed buckyball-like proteins is that one could engineer their interior to be sufficiently hydrophilic that GFP fluorescence would survive complete dehydration of the surrounding tissue, instead relying on the polarized residues of the amino acids in the interior. This would let us combine highest quality EM with highest quality light microscopy in the same sample -- which would be very useful indeed.

dekhn 10y ago
I doubt you could avoid diffusion in these proteins to the point you desire. It would be worth looking into species that exploit cryptobiosis, specifically anhydrobiosis (rotifers, tardigrades, daphnia, and C. Elegans are all examples). In most cases they can dessicate extremely, some of them by exchanging glucose or water with trehalose (itself a fascinating topic worth further study), so i wonder if you could make trehalose binding sites inside the body.

lrc 10y ago

Reminds me of the Andromeda Strain (except that didn't have any amino acids) http://mymeaningfulmovies.blogspot.com/2015/02/the-andromeda-strain.html http://mymeaningfulmovies.blogspot.com/2015/02/the-andromeda...

derogator 10y ago

For anyone paying attention, the dearth of comments in this thread is a key indicator that the most commented threads on HN are all bike shedding threads. A topic like this suffers from high barriers that prevent the formation of opinions, whereas today's Pardon Snowden thread[0] provides ample opportunity for lengthy editorials. [0] https://news.ycombinator.com/item?id=12494998 https://news.ycombinator.com/item?id=12494998

OrthoMetaPara 10y ago

The fact that you can tack on an extra protein domain to each protein subunit is really neat because it lets you assemble little macromolecules containing several custom functionalities. Presumably these extra domains face outwards, coating the surface of the cage. Hopefully these extra domains don't interfere with the cage assembly process. For example, say you created fusions between the cage mononmer and antibody Fv chains that bind two different proteins (A and B) and then you created fusions between the cage monomer and two different fluorescent proteins (GFP and RFP). In bacteria strain 1, you express fusion A and fusion GFP so that you assemble cages that will show a green signal where-ever A is found (e.g., for fluorescent microscopy). Likewise, in bacterial strain 2, you expression fusions B and RFP so that you get a red signal where ever B is. You could use these as detectors in a western blot, for example. (Obviously there are better, established ways to detect proteins of interest in a western blot, but that's just a simple idea). Another idea that I remember reading about was creating glucuronidase fusions to antibody fragments designed to bind cancer cells. The patient would then be administered the glucuronide of a cytotoxic drug, which is not toxic in its glucuronide form. The idea is that the antibody fusion protein would activate the drug so that it would be concentrated highly near the cancer cell and nowhere else.