Researchers spot a new code in disordered proteins

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Even by the standards of the genre, that is hilariously bad.


What is most interesting about the underlying study is how solidly it refutes the ID model of protein structure to function relationships and FI. Of course, we’ve been pointing to IDPs over and over. I’m not sure they have made the conceptual connection yet.


True. I don’t see how this study refutes the ID model of protein structure to function relationships and FI. For example, could you explain how it refutes @gpuccio methodology for assessing FI?

My goodness that was the most confused pile of nonsens I’ve read in a long time. Barely a single sentence in that “article” is not somehow misleading, or confused, or just plain wrong.

It almost reads like an attempt to get out in front of what is essentially evidence against much of the ID nonsense we’ve heard about protein sequence space. Hey, this is evidence against all the things people like Doug Axe, Ann Gauger, and Stephen Meyer have said in their books about the necessity of stable folds for functional proteins, so lets just instead go and say this is somehow (for reasons that aren’t made clear) evidence for ID instead. And lets make sure to try to invert the history and pretend it’s those silly evolutionists who dismissed IDP as “junk DNA”(wat?).

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Yeah the whole idea is that an amino acid sequence that lacks a well-defined, stable, 3dimensional structure, can incrementally be evolved towards a functional fold through these different stages. All while retaining some beneficial function throughout this structural transition.

This runs completely counter to the ID model of the relationship between protein structure and function, as exhibited by the output of people like Douglas Axe and Ann Gauger. In particular you can read Meyer’s book Darwin’s Doubt which discusses Axe’s assertions in some length.

This nonsense is also occasionally output by other people at EN&V, such as this:

This trend in destabilization is remarkably consistent across different types of proteins, as confirmed by both experiment and the FoldX computational algorithm. Of particular importance, the average drop in stability (change in free energy of folding) per mutation is approximately 1 kcal/mol, and the difference in free energy between the folded and unfolded protein states is typically only 3-10 kcal/mol. In addition, roughly two-thirds of mutations are destabilizing (stability drop > 1 kcal/mol) which explains the observation that the same fraction of mutations to a barely functional protein inactivate it. Moreover, the related rarity of proteins has been further confirmed by a residue-residue co-evolutionary statistical model. As a result, a few dozen random mutations would completely disable (unfold) most proteins.

Or this:

This paper is interesting because it relates to the work of Douglas Axe that resulted in a paper in the Journal of Molecular Biology in 2004. Axe answered questions about this paper earlier this year, and also mentioned it in his recent book Undeniable (p. 54). In the paper, Axe estimated the prevalence of sequences that could fold into a functional shape by random combinations. It was already known that the functional space was a small fraction of sequence space, but Axe put a number on it based on his experience with random changes to an enzyme. He estimated that one in 10^74 sequences of 150 amino acids could fold and thereby perform some function — any function.

It is pretty clear that ID proponents think proteins must fold into complex, stable, 3dimensional structures to have any function. And that sequences that can do this are extremely rare and isolated in sequence space. And that to get such a sequence, you need it basically all at once in one go, you can’t gradually evolve towards it because, ID proponents think, all the intermediate stages are nonfunctional.

All of which is of course diametrically opposite to demonstrable fact. And now there’s yet another paper demonstrating the opposite, so the propaganda institute at EN&V is trying the old Orwellian tactic of saying this is all somehow the opposite of what it is(we knew it all along). There’s been a stream of articles over on EN&V full of after-the-fact rationalizations about how intrinsically disordered proteins are now suddenly, somehow, all confirmations of ID. But if you go read the ID literature, you will find no mention of them chronologically prior to these recent papers.

I don’t think this has much to do with Gpuccio’s methodological inability to estimate FI, though.

Heres axe’s response to IDPs

It has quite a bit to do with it. It demonstrates there is a combinatorially large number of functional peaks.

My understanding is that the sequences of these so called disordered protein regions are important for performing their functions. If true, and I think it is true since mutations in these region seem to be associated with diseases, it means that it is probably not true that, as far as disordered protein regions are concerned, there is a combinatorially large number of functional peaks.

That is not a valid argument @Giltil. Sorry.

Your understanding differs from the understanding of those who actually work on such regions. Their understanding is that the disorder is more important than specific sequences.

You’re just asserting your antecedent, Gil. You and @gpuccio aren’t even trying to estimate the proportion of sequence space that is functional. I think you’re afraid to find out.

I’ve spent decades studying what mutations do to the function of proteins. And you?