15 thoughts on “Origins of Life: The Protein Folding Problem all over again”

1. Hi petrushka,

   This is an excellent article. I especially liked this quote:

   …[T]he solution to the physical folding problem, of the driving forces and kinetic routes, is now well-known* (14–18), and it gives useful insights for the OOL [origin of life]. In short, needles-in-haystacks and golf courses are now seen as just incorrect conceptualizations. The problem is not one of random independent steps; the problem is to find what types of physical cooperativity cause the snowballing, or bootstrapping, of one state of small probability to another state of higher probability. Fig. 2 shows three lessons from the PFP: 1) That a physical code, based on hydrophobic (H) and polar (P) patterning reduces the haystack by more than 100 orders of magnitude, as confirmed by experiments (26–30). 2) That the landscape is relatively funnel-shaped, not golf-course-like, because of physical cooperativities in secondary and tertiary drivers (16, 17, 31). 3) That the kinetics is local first, global later; helices and turns early, tertiary structure later (32); reducing an NP-completeness challenge to an often very fast process. In the Foldon Funnel Model, the early fast steps (helices and turns) are not stable (i.e., not downhill); they are just less unstable, continuing up a landscape of diminishing steepness until reaching a tipping point at which full stability is achieved by the native structure (33).

   Cheers.

2. How very odd. The exact same authors have a paper saying basically the same thing in Royal Society:
   The prebiotic emergence of biological evolution

   Funnily enough the first few sentences of the introduction convey exactly the same information, just rephrased.

   Compare these first few sentences of the introductions. The PNAS paper:
   “No one knows how life originated—presumably on earth—about 3.5 to 3.8 billion years ago (1–3). No experiment has rediscovered it. In that breach, modeling can give some guidance. “

   Now from the Royal Society paper:
   “It is not known how life arose from prebiotic matter 3.5 billion years ago. It has not been replicated in a laboratory. In the absence of experiments, there is a role for theory and modelling to help generate hypotheses.”

   They do deviate a bit more hereafter, though it’s really just the same paper rephrased and with a bit of elaboration in one rather than the other here or there.

3. Meh. RNA First. Simples!

   Seriously though, there is a massive transition problem with proteins-first. Proteins, as we know them, are built on nucleic acid sequences. I have yet to see a plausible transition from a hypothetical precursor that reproduced by some mysterious means and specified protein sequence by some other mysterious means, to the system we have today.

   This also solves the chirality problem, and the alpha-amino-acid problem. Granted that it has problems of its own… But it seems pretty clear (to me) that modern protein is an outgrowth of RNA processing, and not the other way round. Its ubiquity tempts people to insist it must be fundamental, but I think Life needed to walk before it could run.

4. and not the other way round. Its ubiquity tempts people to insist it must be fundamental, but I think Life needed to walk before it could run.

   This is the simple to complex model. How do you propose something like the transcription and translation mechanism could come into existence without some intelligence behind it?

5. Allan Miller:
   Meh. RNA First. Simples!

   Seriously though, there is a massive transition problem with proteins-first. Proteins, as we know them, are built on nucleic acid sequences.

   Agreed, but nucleic acid sequences (well the nitrogenous bases specifically) are biosynthesized from amino acids in all organisms that do de novo synthesis. Curious fact.

   Allan Miller:
   I have yet to see a plausible transition from a hypothetical precursor that reproduced by some mysterious means and specified protein sequence by some other mysterious means, to the system we have today.

   I think your use of the word “plausible” is doing some potential work here. The papers described in the OP offer one such mechanism, but you don’t find it plausible so the matter is thereby settled?

   Interestingly they’re not saying any particular protein sequence was specified and reproduced over and over, but rather through mutual catalysis and cooperative folding, certain catalysts were. It’s a model that posits that evolution and reproduction took place before sequence specificity.

   Allan Miller:
   This also solves the chirality problem

   Well you need homochiral D-ribose for RNA. You too must appeal to some sort of scenario for how homochiral monomers were produced. Infamously racemic mixtures of RNA monomers stall chain elongation.

   Allan Miller:
   Its ubiquity tempts people to insist it must be fundamental, but I think Life needed to walk before it could run.

   I think it’s actually more strongly motivated by the observation that amino acids are found in things like meteorites and routinely produced in various sorts “hands-off” experiments in abiotic chemistry (and that amino acids are chemical precursors of RNA bases in known pathways of de novo biosynthesis), whereas RNA is not, and synthetic organic chemists have had to construct some quite elaborate discontinuous pathways of synthesis and then provided some rather ad-hoc stories about various series of geochemical and atmospheric events to drive these syntheses.

6. Rumraket: Agreed, but nucleic acid sequences (well the nitrogenous bases specifically) are biosynthesized from amino acids in all organisms that do de novo synthesis. Curious fact.

   Not saying amino acids weren’t available. Just coded proteins

   I think your use of the word “plausible” is doing some potential work here. The papers describedin the OP offer one such mechanism, but you don’t find it plausible so the matter is thereby settled?

   I don’t see the transition to nucleic acid and NA-encoded proteins there.

   Well you need homochiral D-ribose for RNA.

   It’s worse than that! There are 4 chiral centres, 16 isomers.

   You too must appeal to some sort of scenario for how homochiral monomers were produced. Infamously racemic mixtures of RNA monomers stall chain elongation.

   True, I have yet to solve OoL. I think there is some mileage in complementarity, however. I think complementarity is fundamental, not derived. Kinked chains would be less stable, and not pair, which is itself a stabilising interaction.

   think it’s actually more strongly motivated by the observation that amino acids are found in things like meteorites and routinely produced in various sorts “hands-off” experiments in abiotic chemistry (and that amino acids are chemical precursors of RNA bases in known pathways of de novo biosynthesis), whereas RNA is not, and synthetic organic chemists have had to construct some quite elaborate discontinuous pathways of synthesis and then provided some rather ad-hoc stories about various series of geochemical and atmospheric events to drive these syntheses.

   Amino acids are thermodynamically favoured, hence they appear so readily in meteorites and Miller’s flasks. And hence are available as ribonucleotide precursors. But chaining them is not. Nucleic acid monomers, otoh, come equipped with the energy of their own extension.

7. colewd: This is the simple to complex model.How do you propose something like the transcription and translation mechanism could come into existence without some intelligence behind it?

   I don’t know how ‘intelligence’ goes any way to solving the problem. It’s not an answer to anything.
   “How did this happen?”.
   “Intelligence”
   “Righto. Clear as mud”.

8. Rumraket:
   How very odd. The exact same authors have a paper saying basically the same thing in Royal Society:
   The prebiotic emergence of biological evolution

   Funnily enough the first few sentences of the introduction convey exactly the same information, just rephrased.

   Compare these first few sentences of the introductions. The PNAS paper:
   “No one knows how life originated—presumably on earth—about 3.5 to 3.8 billion years ago (1–3). No experiment has rediscovered it. In that breach, modeling can give some guidance. “

   Now from the Royal Society paper:
   “It is not known how life arose from prebiotic matter 3.5 billion years ago. It has not been replicated in a laboratory. In the absence of experiments, there is a role for theory and modelling to help generate hypotheses.”

   They do deviate a bit more hereafter, though it’s really just the same paper rephrased and with a bit of elaboration in one rather than the other here or there.

   Are you ready to be injected with mpox “vaccine”? The science you devoted yourself to tells you to get it. What are your thoughts?

9. Allan Miller,

   How do you know the mRNA “vaccine” delivered?

10. Allan Miller,

    I don’t know how ‘intelligence’ goes any way to solving the problem. It’s not an answer to anything.
    “How did this happen?”.
    “Intelligence”
    “Righto. Clear as mud”.

    The inference of intelligence may be suggesting we are chasing windmills with this project and resources are better spent elsewhere.

11. J-Mac:
    Allan Miller,

    How do you know the mRNA “vaccine” delivered?

    What in fuck does this have to do with protein folding at OoL?

12. colewd:
    Allan Miller,

    The inference of intelligence may be suggesting we are chasing windmills with this project and resources are better spent elsewhere.

    It doesn’t though. Intelligence (as far as we know) can only rearrange matter. It can’t generate matter (or rather mass-energy) from nothing. It can’t get carbon to behave one way in one compound, but another incompatible way in another. So ‘intelligence’ is just another mechanistic theory, at heart. Its proponents don’t recognise this, of course, they think it can all be ‘shazam-ed’ into existence by super-intelligence.

13. Allan Miller,

    It doesn’t though. Intelligence (as far as we know) can only rearrange matter. It can’t generate matter (or rather mass-energy) from nothing. It can’t get carbon to behave one way in one compound, but another incompatible way in another. So ‘intelligence’ is just another mechanistic theory, at heart. Its proponents don’t recognise this, of course, they think it can all be ‘shazam-ed’ into existence by super-intelligence.

    I agree that intelligence as far as we know it cannot produce matter from nothing.

    The problem with OOL is where is the real starting point at which we can do science. For all practical purposes for living organisms it is the cell.

    The starting points for biology appear to be the cell and for physics the starting point appears to be the atom. Trying to figure out the origin of these fundamental components appears to be beyond our capability.

14. colewd:
    Allan Miller,

    I agree that intelligence as far as we know it cannot produce matter from nothing.

    The problem with OOL is where is the real starting point at which we can do science.For all practical purposes for living organisms it is the cell.

    The starting points for biology appear to be the cell and for physics the starting point appears to be the atom.Trying to figure out the origin of these fundamental components appears to be beyond our capability.

    But this is where the ‘intelligence’ argument fallls off the rails. It is a Trojan Horse for pure Creationism, ex nihilo. If we allow that the space of possible carbon molecules and systems (circumscribed by the quantum numbers of its fundamental particles), includes true replicators, then there is no a priori reason for supposing that these points in space can only be reached by some entity willing it.

15. Allan Miller,

    But this is where the ‘intelligence’ argument fallls off the rails. It is a Trojan Horse for pure Creationism, ex nihilo

    It can be a Trojan Horse.

    It can also be a useful tool for knowing where to apply resources by helping understanding scientific starting points.