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Comment by trott | Hacker News Reader

> matching less than 60% of the sequence of the most closely related fluorescent protein

> When the researchers made around 100 of the resulting designs, several were as bright as natural GFPs, which are still vastly dimmer than lab-engineered variants.

So they didn't come up with better functionality, unlike what some commentators imply. They basically introduced a bunch of mutations while preserving the overall function.

Relevant: https://en.wikipedia.org/wiki/Conservative_replacement

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60% is freaking nothing in protein space. Like, that's not something to brag about. I could go through and hand edit GFP to 60% identity and get basically GFP still functional at the end.

In grad school, I worked on proteins that were 12%-15% sequence identical but had sub 4 Å RMSDs once the structures were solved.

EDIT: Actually, bragging about it could be a nigerian prince thing, where they do it to scare away investors that might actually hold them to some standard.

If the mutations were non-synonymous, resulting in different amino acids, the fact that they keep the natural function is still kinda cool. Very much a pure research result AFAICT, but worth a little something.

This is already a well known fact: protein structure (and consequently function) is much more conserved than sequence, mostly due to biophysical constraints.

Forgive my ignorance - is that true even for non-synonymous mutations? They usually have a hard time disrupting the big structure?

If non-synonymous mutations do not change the biophysical features of the amino acid residues, then the structure is usually kept. Alternatively, it can be the case that a disruptive mutation is compensated by another one that keeps the structure/function/phenotype. This is the basis for evolutionary coupling based structure prediction methods, such as Alphafold.

It's fairly common for two proteins to have almost identical structures but different (down to 30% or lower sequence identify) and it's also possible to mess up a nice protein that folds easily with a single amino acid change.

Depends entirely on the context and details.

That's still a pretty significant result. Imagine how much more effective directed evolution could be if it weren't driven by random mutation, or if the random mutations were applied on top of already working variants.

That feels like deliberately cute wording. What was the similarity vs the starting molecule? I could probably hand pick a few point mutations substituting one small hydrophobic AA for another without impacting function.

You’d be surprised by how many failures you get by such an approach. Hydrophobic cores can be easily disrupted by altering some side chain volumes.

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