6 ms·

Tiny ion is crucial for HIV replication, say chemists

108 points by wglb 4y ago

mkl 4y ago
Is there such a thing as a non-tiny ion? I suppose a very long carbon chain might count. It's strange that the article doesn't even name it: inositol hexakisphosphate, a.k.a phytic acid https://en.wikipedia.org/wiki/Phytic_acid https://en.wikipedia.org/wiki/Phytic_acid.
- ben_w 4y ago
  Albeit as a non-chemist, I'm surprised ions get as big as phytic acid.
  - psychphysic 4y ago
    I'm not a chemist. But by common definitions aren't all acids (an)ions? (As in bronstead Lowry acids). So why is it being called an ion and not just acid?
    - mkl 4y ago
      I think because they're talking about individual molecules fitting into the solid structure, not lots of molecules in solution.
    - cout 4y ago
      I am also not a chemist. A (bronstead) acid is a proton donor. An atom that donates a proton becomes an (an)ion. The acid is not the anion; the anion is the conjugate base of the acid. Not all acids form an anion; hydronium is an ion that becomes neutral when it donates a proton. I do not know why the article used the term ion here. I am guessing it is because the abstract refers to IP6 as a polyanion. It is not referred to as an acid, because it is not participating in acid/base chemistry (though I tried reading the paper and the mechanism is well over my head).
      - nextaccountic 4y ago
        > An atom that donates a proton An atom can donate an electron (and become a cation), but how can an atom donate a proton? By nuclear fission? edit: but, a molecule can donate a proton (an H+), and the molecule itself will become an anion
        cout 4y ago
        Good point, I meant to say molecule, not atom. I blame lack of coffee.
- ginko 4y ago
  > It's strange that the article doesn't even name it: inositol hexakisphosphate, a.k.a phytic acid That actually seems pretty large as ions go. Compared to inorganic ones at least.
  - feet 4y ago
    Yea when I read "tiny ion" I think "oh something like a sodium or potassium ion"
- dmitryminkovsky 4y ago
  I didn't know people used the term "ion" like this, either.
- candiodari 4y ago
  I think the general idea is that the biggest ion 2 angstrom tops, more likely 0.2 angstrom, whereas most proteins (where the ion is used) are 30-50 angstroms across (and note this is 3d, a 1 angstrom ion is 1000 times smaller than a 10 angstrom protein). And the whole HIV virus particle is ~1200 angstrom across. So that ion is like a mouse compared to a skyscraper.
scotty79 4y ago
Not sure how could this lead to any treatment. I don't think we can just knock out production of IP6. It's produced in the body so it probably has some role there. We'd have to target hiv infected cells specifically and if we could do that then why not just kill them.
- Scaevolus 4y ago
  FTA > The result may explain the promise of a drug currently in human trials: lenacapavir. Lenacapavir "competes" with IP6, stabilizing the six-sided structures over the five-sided ones. This tilts the process to favor open-ended tube shapes instead of enclosed capsids.
  - epmaybe 4y ago
    Just a small note - lenacapavir has been approved by the FDA since December 2022
chucklenorris 4y ago
Can someone explain how these proteins get to form the capsid structure? Do they just float around in the cytoplasm and self-assemble through molecular forces? Or there are other specialized machines that do the assembling? How are the machines produced in the first place? It seems so improbable, like throwing a bunch of bricks near each other and getting a house
- comboy 4y ago
  I won't pretend to be able to give an accurate answer but if you wonder about this kind of things, this book is a masterpiece [1]. Yes, it's expensive and big, but also fascinating and very well prepared. https://www.amazon.com/Molecular-Biology-Sixth-Bruce-Alberts/dp/0815345240 https://www.amazon.com/Molecular-Biology-Sixth-Bruce-Alberts...
  - victor106 4y ago
    great recommendation. from that book "We can take a piece of DNA from a human cell and insert it into a bacterium or a piece of bacterial DNA and insert it into a human cell, and, with only a few minor modifications, the information will be successfully read, interpreted, and copied" that is truly amazing...
- DrAwdeOccarim 4y ago
  You've got the idea! I'm not an HIV biologist, but typically these viruses utilize poly-cistronic transcripts. What that means is the proteins are made off the same mRNA so when they come off the ribosome they are local to the previous and next proteins being decoded. It's a very recurring theme in biology to have high _local_ concentration of things that you'd like to do a thing together. Imagine a box of magnitiles that you just start throwing around the room. Well, instead of throwing them around the room and hoping they stick to each other, what if you only threw them around inside another box, which you were shaking vigorously? Well, you'd expect the magnitiles to find each other and stick to each other. Now imagine you attach each magnitile by a 1cm string and then throw them into a box and right after you through a string of 100 magnitiles, you start a new string of 100 magnitiles and throw that into the box instead of throwing it at the other side of the room. The idea being concentration depends on the denominator of the volume you're in. If you have 2 things in a 1x1 meter box, you have a much higher concentration and therefore it is much more likely two things will bump into each other a lot than if you have 2 thing in a 1000 x 1000 meter box. Also, a lot of these systems get made on the endoplasmic reticulum and so it then becomes a 2D search problem instead of a 3D search problem, reduces the volume of your box by an entire dimension! AND viruses tend to make little cordon off spots inside the cell where all their bits congregate, further increasing the chances they bump into each other the right way because, again, the _local_ concentration is super, super high. Also keep in mind things at this scale bump into each other a mind boggling number of times per unit time. Like an asstillion number of times every second. Eventually they hit each other in the right way to stick together like magnitiles. They also vibrate constantly, which is called "exploring the conformational space". Anyway, I think you see my points.
phkahler 4y ago
My first question would be: What if you increase the concentration of IP6? The idea being to promote the creation of many 5-sided things, increasing curvature all over and creating capsids too small to enclose the genetic material. If nothing else, the standard downside would apply: IP6 is not a novel molecule and would probably not be patentable.

108 points by wglb 4y ago

mkl 4y ago

Is there such a thing as a non-tiny ion? I suppose a very long carbon chain might count. It's strange that the article doesn't even name it: inositol hexakisphosphate, a.k.a phytic acid https://en.wikipedia.org/wiki/Phytic_acid https://en.wikipedia.org/wiki/Phytic_acid.

ben_w 4y ago
Albeit as a non-chemist, I'm surprised ions get as big as phytic acid.
- psychphysic 4y ago
  I'm not a chemist. But by common definitions aren't all acids (an)ions? (As in bronstead Lowry acids). So why is it being called an ion and not just acid?
  - mkl 4y ago
    I think because they're talking about individual molecules fitting into the solid structure, not lots of molecules in solution.
  - cout 4y ago
    I am also not a chemist. A (bronstead) acid is a proton donor. An atom that donates a proton becomes an (an)ion. The acid is not the anion; the anion is the conjugate base of the acid. Not all acids form an anion; hydronium is an ion that becomes neutral when it donates a proton. I do not know why the article used the term ion here. I am guessing it is because the abstract refers to IP6 as a polyanion. It is not referred to as an acid, because it is not participating in acid/base chemistry (though I tried reading the paper and the mechanism is well over my head).
    - nextaccountic 4y ago
      > An atom that donates a proton An atom can donate an electron (and become a cation), but how can an atom donate a proton? By nuclear fission? edit: but, a molecule can donate a proton (an H+), and the molecule itself will become an anion
      - cout 4y ago
        Good point, I meant to say molecule, not atom. I blame lack of coffee.
ginko 4y ago
> It's strange that the article doesn't even name it: inositol hexakisphosphate, a.k.a phytic acid That actually seems pretty large as ions go. Compared to inorganic ones at least.
- feet 4y ago
  Yea when I read "tiny ion" I think "oh something like a sodium or potassium ion"
dmitryminkovsky 4y ago
I didn't know people used the term "ion" like this, either.
candiodari 4y ago
I think the general idea is that the biggest ion 2 angstrom tops, more likely 0.2 angstrom, whereas most proteins (where the ion is used) are 30-50 angstroms across (and note this is 3d, a 1 angstrom ion is 1000 times smaller than a 10 angstrom protein). And the whole HIV virus particle is ~1200 angstrom across. So that ion is like a mouse compared to a skyscraper.

scotty79 4y ago

Not sure how could this lead to any treatment. I don't think we can just knock out production of IP6. It's produced in the body so it probably has some role there. We'd have to target hiv infected cells specifically and if we could do that then why not just kill them.

Scaevolus 4y ago
FTA > The result may explain the promise of a drug currently in human trials: lenacapavir. Lenacapavir "competes" with IP6, stabilizing the six-sided structures over the five-sided ones. This tilts the process to favor open-ended tube shapes instead of enclosed capsids.
- epmaybe 4y ago
  Just a small note - lenacapavir has been approved by the FDA since December 2022

chucklenorris 4y ago

Can someone explain how these proteins get to form the capsid structure? Do they just float around in the cytoplasm and self-assemble through molecular forces? Or there are other specialized machines that do the assembling? How are the machines produced in the first place? It seems so improbable, like throwing a bunch of bricks near each other and getting a house

comboy 4y ago
I won't pretend to be able to give an accurate answer but if you wonder about this kind of things, this book is a masterpiece [1]. Yes, it's expensive and big, but also fascinating and very well prepared. https://www.amazon.com/Molecular-Biology-Sixth-Bruce-Alberts/dp/0815345240 https://www.amazon.com/Molecular-Biology-Sixth-Bruce-Alberts...
- victor106 4y ago
  great recommendation. from that book "We can take a piece of DNA from a human cell and insert it into a bacterium or a piece of bacterial DNA and insert it into a human cell, and, with only a few minor modifications, the information will be successfully read, interpreted, and copied" that is truly amazing...
DrAwdeOccarim 4y ago
You've got the idea! I'm not an HIV biologist, but typically these viruses utilize poly-cistronic transcripts. What that means is the proteins are made off the same mRNA so when they come off the ribosome they are local to the previous and next proteins being decoded. It's a very recurring theme in biology to have high _local_ concentration of things that you'd like to do a thing together. Imagine a box of magnitiles that you just start throwing around the room. Well, instead of throwing them around the room and hoping they stick to each other, what if you only threw them around inside another box, which you were shaking vigorously? Well, you'd expect the magnitiles to find each other and stick to each other. Now imagine you attach each magnitile by a 1cm string and then throw them into a box and right after you through a string of 100 magnitiles, you start a new string of 100 magnitiles and throw that into the box instead of throwing it at the other side of the room. The idea being concentration depends on the denominator of the volume you're in. If you have 2 things in a 1x1 meter box, you have a much higher concentration and therefore it is much more likely two things will bump into each other a lot than if you have 2 thing in a 1000 x 1000 meter box. Also, a lot of these systems get made on the endoplasmic reticulum and so it then becomes a 2D search problem instead of a 3D search problem, reduces the volume of your box by an entire dimension! AND viruses tend to make little cordon off spots inside the cell where all their bits congregate, further increasing the chances they bump into each other the right way because, again, the _local_ concentration is super, super high. Also keep in mind things at this scale bump into each other a mind boggling number of times per unit time. Like an asstillion number of times every second. Eventually they hit each other in the right way to stick together like magnitiles. They also vibrate constantly, which is called "exploring the conformational space". Anyway, I think you see my points.

phkahler 4y ago

My first question would be: What if you increase the concentration of IP6? The idea being to promote the creation of many 5-sided things, increasing curvature all over and creating capsids too small to enclose the genetic material. If nothing else, the standard downside would apply: IP6 is not a novel molecule and would probably not be patentable.