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Our paper on a hydrophobic ratchet that preserves useless molecular complexity is out in Nature today. I am excited and nervous in equal parts. A not so short thread on what we found. https://www.nature.com/articles/s41586-020-3021-2
How biological complexity arises and persists is a fundamental question in evolution. Protein complexes are a common example of such complexity. The interfaces that hold them together contain many intricate parts that seem like they could easily be destroyed by mutation.
What protects them against the constant hail of destructive mutations? I think us biochemists instinctively reach for adaptationist explanations: protein complexes persist because they must be useful. Useful functions could include allostery, stability, regulation, etc.
But for a good number of complexes we don’t know of functional advantages. Maybe we just haven’t looked hard enough? Our paper provides an alternative, based on very simple principles of biochemistry and classical evolutionary theory.
Using the example of steroid receptors, we found that if a complex evolves a hydrophobic interface, it becomes very difficult to lose that interface, because exposed hydrophobics lead to misfolding and aggregation.
To go back to being a monomer, you’d have to get rid of all the hydrophobics first. How likely is that? We used existing data on how likely different kinds of mutations are to figure out what a surface would look like if it were allowed to mutate freely.
We found that that such a surface would be very hydrophobic. Much more so than exposed protein surfaces actually are. This means that the mutational process is very unlikely to return an interface to a composition that is safe for exposure to water.
Once an interface is hydrophobic, it is therefore likely going to stick around, even if it never did anything useful, or if it ceases to do so later. We did additional bioinformatic analysis that suggests many protein families have interfaces that show signs of entrenchment.
So far for the results. I want to take this opportunity to stress what we think this work means, but also crucially what it does not mean.
I think our work shows that complexes can in principle exist even if they do not provide functional advantages over monomers. This is not the first ratchet preserving useless complexity we know of. Think of subfunctionalization of duplicated genes as one example.
I think we should treat entrenchment as a null hypothesis for the persistence of complexes. If you have no other explanation for why a complex exists, entrenchment provides a universal and simple explanation. If you suspect it’s useful, you should supply evidence.
Now to what our work does not imply: We are agnostic about what causes the initial evolution of interfaces -selection or drift. Entrenchment is concerned only with their subsequent preservation. My lab is currently working on if complexes can arise neutrally.
Entrenchment also does not preclude adaptation. Natural selection can attach useful functions to complexes that are also hydrophobically entrenched. This may be true for very many complexes. Presently I remain agnostic about what fraction of complexes are useful.
Finally, I just want to shout out the work of Michael Lynch, Ford Doolittle, and Arlin Stolzfuß, which was a major inspiration for this work.
Last but but not least,a huge thanks you to my co-authors Yang,Erik, Brian, Art and of course Joe.
And here is the press release on our MPI website https://www.mpi-marburg.mpg.de/988365/2020-12-b
