Mercer's Work on Protein Function and Sequence Space

[swamidass (S. Joshua Swamidass)]

Continuing the discussion from Gauger and Mercer: Bifunctional Proteins and Protein Sequence Space:

@JAMercer

I’d like to present a summary of our work for discussion.

This has the same general thrust as Art Hunt’s critique–

https://discourse.peacefulscience.org/t/art-hunt-to-doug-axe-invitation-to-discuss/
https://discourse.peacefulscience.org/t/side-comments-on-hunt-to-axe/

but is a series of empirical demonstrations to complement Art’s more theoretical criticisms.

It’s also relevant to this other discussion:

https://discourse.peacefulscience.org/t/the-probability-of-a-bifunctional-protein/

as we made bifunctional proteins very easily.

@JAMercer, I’m looking forward to the exchange with @Agauger. Hopefully Doug Axe will join too, as he is the one who has been pushing this work the most in his book, Undeniable. She can’t engage in depth right now, but in the mean time, can you expand on your work here?

Here are some of the summaries you already have:

@JAMercer

Our goal was not to learn anything about evolution, but to address a problem in biology caused by evolution: there are huge multigene families that according to sequence relationships and everything else, are the result of gene duplications and diversifications of function. However, contrary to the machine-like picture painted by the ID folks, these functional diversifications are rarely complete, leaving us with schmeers of partially overlapping functions, something we simply don’t see in designed machines. It just screams that it could only have been designed by the iterative process of evolution, much louder than the ID refrain that life is like some sort of human-designed machine.

And one example. Can you explain this paper further, and put the key figures up here too? After, this, what are the next key papers to look at?

@JAMercer

The idea here was spatial and fairly simple: we identified a bulky tyrosine residue found in most but all myosins–not only right in the most sensitive part, the active site, but associated with the substrate ATP–and changed it to the least bulky residue, glycine (Y61G or Tyr61Gly). Without changing the charge, this was the most radical size change possible. We basically turned a bump in the active site into a hole. More than one myosin turned out to be far more resilient than we ever would have predicted.

The engineering goal was to make a mutant that had two properties: 1) normal wild-type function, and 2) the ability to recognize ATP and ADP modified with a bulky N6 addition (fitting where the tyrosine side chain was missing in the mutant) that would have no effect on the wild-type myosin because it wouldn’t fit in the active site.

This was amazingly easy because it worked with the very first substitution we tried

http://www.jbc.org/content/274/44/31373.full

[Mercer (John Mercer)]

I think we should wait until Ann is able to participate.

[Michael_Okoko]

It appears she refused to continue the conversation, but I would like to know more.

[Mercer (John Mercer)]

Search in other threads for our names.

[Chris_Falter]

I have heard that @Agauger has had some health problems, so it is almost certainly not a refusal on her part.

Personally, I said a prayer for her as I wrote this.

Chris

[Michael_Okoko]

Oh. I hope she recovers soon if so.