# The Argument Clinic

**URL:** <https://discourse.peacefulscience.org/t/the-argument-clinic/15561>\
**Category:** Side Conversation\
**Tags:** Comments\
**Created:** [November 22, 2022, 2:16pm UTC](https://discourse.peacefulscience.org/t/the-argument-clinic/15561 "2022-11-22T14:16:20Z")\
**Posts on this page:** 1\
**Showing post:** 2579

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**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [June 1, 2024, 5:07pm UTC](https://discourse.peacefulscience.org/t/the-argument-clinic/15561/2579 "2024-06-01T17:07:54Z")

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> [@Rumraket](#):
>
> I must repeat my request for you to stop assigning views to me I do not hold.

You fried my irony meter there.

> [@Rumraket](#):
>
> Shall we now also go over, again, how you personally having [characterized the effect of a small handful of mutations to α-tropomyosin and found 8 stabilizing](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/63) rather than destabilizing,

Let’s. Just to be clear, I didn’t do it personally. I supervised the postdoc and students who did the hands-on work.

> [@Rumraket](#):
>
> doesn’t actually allow you **to extract _a general trend_ for the stability-effects of mutations on protein structure** ,

I didn’t. I was very clear about that in the very thread you linked to above:

> [@Detwiler: Questions Behe, Polyphen, and Ratchets](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/97):
>
> > [@Detwiler: Questions Behe, Polyphen, and Ratchets](https://discourse.peacefulscience.org/t/detwiler-questions-behe-polyphen-and-ratchets/5088/63):
> >
> > Which is interesting and curious in it’s own right I agree, but that hardly constitutes a trend I feel comfortable extrapolating to a general phenomenon for most proteins.
> 
> I don’t think it’s that curious. I think that my saying that the direction of a process is basically 50/50 is saying that there’s NOT a trend.

LOL. Was that not clear, Mikkel?

I cited our work because finding 8 of 8 disease-causing mutations increasing stability was _ **unremarkable** _.

Active-site changes that decrease function pretty consistently increase stability. We’ve known this for a very long time. One old example:

[https://www.pnas.org/doi/epdf/10.1073/pnas.92.2.452](https://www.pnas.org/doi/epdf/10.1073/pnas.92.2.452)

For large collections of hypomorphic alleles (for example G6PD, because deficiency protects against malaria), there appear to be groupings with differing relationships between stability and function:

[https://www.cell.com/cell-reports/fulltext/S2211-1247(17)30246-2](https://www.cell.com/cell-reports/fulltext/S2211-1247(17)30246-2)

And it’s not limited to mutations. You can do a control PCR reaction to measure the activity vs. stability of Taq DNApol at different temperatures in an afternoon. Stabilizing the most abundant family of proteins in your body, the collagens, by glycation caused by excess glucose causes enormous human suffering in people with diabetes.

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