iiinova — where your digital self keeps evolving

Sam Berry @sberry.bsky.social · 21/04/2026

Finally, I have to shout out everyone who made this possible, especially the endlessly patient @rachellegaudet.bsky.social but also my fearless mentee Camille and far more people than I can fit in this post who gave me neverending help and advice!

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Sam Berry @sberry.bsky.social · 21/04/2026

Why would this happen? At the end, we propose a simple model explaining why the same residues might influence both epistasis and specificity in terms of the energetic balance between the transporter's major conformations. Check out the paper and let me know what you think!

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Sam Berry @sberry.bsky.social · 21/04/2026

Second, we find only a small set of "core" mutations clustered around a key binding site methionine allow for Mg2+ import. However, many additional mutations can then finetune this specificity. What's more, these specificity modulator mutations correlate strongly with those epistatic hotspots (!)

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Sam Berry @sberry.bsky.social · 21/04/2026

First, even though many mutations combine additively, we see specific epistasis at non-contacting positions that clusters at epistatic hotspots around where the transporter protein opens and closes. We see much more of this than has been observed previously for folding or binding domains.

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Sam Berry @sberry.bsky.social · 21/04/2026

If you've read this kind of study before, some trends are obvious by now: mutations to the binding site tend to be deleterious, P/R/K are especially perturbative, the effects of many mutations when combined can be modeled as additive. But where it gets interesting is where those trends break down...

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Sam Berry @sberry.bsky.social · 21/04/2026

To test more than single-mutant effects, we used structural and evolutionary information to guide the library toward combinations of mutations hypothesized to be more likely to alter specificity. This included a combinatorial library across 59 positions informed by natural sequence diversity:

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Sam Berry @sberry.bsky.social · 21/04/2026

We addressed this by developing new assays that allowed us to make thousands of different sequence changes to a model metal transporter and then quantify how those changes affect its import of a representative native metal substrate, Mn2+, as well as a non-transported ion, Mg2+.

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Sam Berry @sberry.bsky.social · 21/04/2026

Transporters must use a limited set of structural scaffolds to accurately discriminate between arbitrary substrates, in the process undergoing major conformational change. Despite advances in machine learning, the "rules" by which transporter sequences encode these functions remain opaque.

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Sam Berry @sberry.bsky.social · 21/04/2026

I'm excited to share our new preprint representing the bulk of my PhD work, along with @camillefreedman.bsky.social, @deboramarks.bsky.social and @rachellegaudet.bsky.social. How do transporter proteins control what molecules they bring across the membrane? www.biorxiv.org/content/10.6...

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Sam Berry @sberry.bsky.social · 07/04/2026

First, even though many mutations combine additively, we see significant specific epistasis at non-contacting positions that cluster at hotspots around where the transporter protein opens and closes. We see much more of this than has been observed for folding or binding domains.

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Sam Berry @sberry.bsky.social · 07/04/2026

If you've read this kind of study before, some trends are obvious by now: mutations to the binding site tend to be deleterious, P/R/K are especially perturbative, the effects of many mutations when combined can be modeled as additive. But it gets interesting where those trends break down...

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Sam Berry @sberry.bsky.social · 07/04/2026

To probe beyond single mutants and understand how mutations combine, we used both structural and evolutionary information to guide our library - including a particularly fun combinatorial library design informed by natural sequence variation enriched for residues more likely to alter specificity

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Reposted by Sam Berry

Debora Marks @deboramarks.bsky.social · 24/11/2025

New paper “Proteome-wide model for human disease genetics” is now live at Nature Genetics: rdcu.be/eRu7K popEVE (pop.evemodel.org) finds the needles in the haystacks of human genetic variation:

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Senator Bernie Sanders @sanders.senate.gov · 10/11/2025

I’m voting no on the continuing resolution that would double healthcare premiums for 20 million Americans, kick 15 million people off Medicaid & allow 50,000 Americans to die unnecessarily every year. All to give $1 trillion in tax breaks for billionaires.

youtube.com

LIVE: I Won't Support Doubling Health Care Premiums

YouTube video by Senator Bernie Sanders

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Sam Berry @sberry.bsky.social · 01/09/2025

Yes, I think I agree. There are two problems: 1) the approach they use isn’t very accurate even for natural proteins and 2) any model will behave very differently for sequences close to the training set than for those far away, so their result is expected just from how the model is trained

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Sam Berry @sberry.bsky.social · 01/09/2025

To my knowledge there is no evidence that that networks like ESMFold accurately predict structural perturbations upon mutation? So yeah seems it’s entirely analysis *of the model* not of actual protein biophysics

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David Ho @davidho.bsky.social · 31/08/2025

RFK Jr. is not a vaccine skeptic. He's a vaccine denier whose anti-science extremist views and actions are destroying one of humanity's greatest scientific achievements. He's going to kill a lot of people, and those deaths are on the 52 Republican senators who confirmed him and those enabling him.

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Sarah Gurev @sarahgurev.bsky.social · 17/08/2025

🚨New paper 🚨 Can protein language models help us fight viral outbreaks? Not yet. Here’s why 🧵👇 1/12

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Pascal Notin @pascalnotin.bsky.social · 18/06/2025

🚨 New paper 🚨 RNA modeling just got its own Gym! 🏋️ Introducing RNAGym, large-scale benchmarks for RNA fitness and structure prediction. 🧵 1/9

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Sam Berry @sberry.bsky.social · 05/06/2025

As a note - AlphaFold and other similar algorithms can still do reasonably well without MSA info. They really have learned principles from the PDB (but these principles are NOT physical protein folding - as evidenced by that they can’t predict destabilizing muts etc)

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Sam Berry @sberry.bsky.social · 30/05/2025

Couldn't be prouder of my incredibly talented mentee Camille and glad to see her hard work has been acknowledged by winning *both* the Hoopes and Henderson prizes for her undergraduate thesis!

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Sam Berry @sberry.bsky.social · 13/05/2025

Lovely article from our colleague Kseniia Petrova, who has been wrongfully imprisoned for months: www.nytimes.com/2025/05/13/o...

nytimes.com

Opinion | The Science I Would Be Doing if I Weren’t in ICE Detention

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Sam Berry @sberry.bsky.social · 04/05/2025

Thanks, will check these out!

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Sam Berry @sberry.bsky.social · 04/05/2025

Do you think it would be be more reasonable to benchmark these kinds of models against raw NMR data (e.g. by simulating NMR data from the predicted ensemble, if that’s possible) or are there still too many sources of variability going into the raw data?

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Nick Polizzi @nickpolizzi.bsky.social · 28/04/2025

Super excited to share a new preprint from our lab on design of small-molecule binding proteins using neural networks! The paper has a bit of everything. A new graph neural network, new design algorithms, and experimental validation. www.biorxiv.org/content/10.1... 🧵🧪

biorxiv.org

Zero-shot design of drug-binding proteins via neural selection-expansion

Computational design of molecular recognition remains challenging despite advances in deep learning. The design of proteins that bind to small molecules has been particularly difficult because it requ...

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Sam Berry @sberry.bsky.social · 01/04/2025

I think it says everything here that the locked-away industry version of AlphaFold3 they want to build is based on... OpenFold, which was developed to be open-source by academics. Industry is built on the advances of open-source research. www.nature.com/articles/d41...

nature.com

AlphaFold is running out of data — so drug firms are building their own version

Thousands of 3D protein structures locked up in big-pharma vaults will be used to create a new AI tool that won’t be open to academics.

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Congresswoman Ayanna Pressley @pressley.house.gov · 29/03/2025

This week, my Somerville constituent Rümeysa Öztürk was abducted in broad daylight by DHS officials and sent to Louisiana to be locked in a detention center. She has not been charged with any crime.

A graphic that reads Free Rümeysa Öztürk with a photo of her.

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Stephanie M. Lee @stephaniemlee.bsky.social · 21/03/2025

"On October 8, 1931, a law went into effect requiring every Italian university professor to sign an oath pledging their loyalty to the government of Benito Mussolini. Out of over 1,200 professors in the country, only 12 refused. All of them were immediately fired." www.chronicle.com/article/what...

chronicle.com

Opinion | What Autocrats Want From Academics: Servility

In 1931, Italian scholars were made to take loyalty oaths. Will that happen to us?

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Sam Berry @sberry.bsky.social · 28/02/2025

Publishing this *now* is so embarrassingly tone-deaf and anti-science I almost can’t believe it - just as this exact ideology is being used in a fascist takeover of the US and the accompanying wholesale attack on science and free speech

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Stephanie Hicks @stephaniehicks.bsky.social · 27/02/2025

Friends, I am at a loss of words for how devastating it would be to lose the entire intramural #NIH program. Some of the biggest medical and scientific breakthroughs have come from scientists in the NIH Intramural program. #SaveTheNIH 🧬🧪 🖥️ 🧠 www.science.org/content/arti...

science.org

NIH ban on renewing senior scientists adds to assaults on its in-house research

Policy follows firings of tenure-track scientists and suspension of training programs

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Alisia Fadini @alisiafadini.bsky.social · 24/02/2025

Structural biology is in an era of dynamics & assemblies but turning raw experimental data into atomic models at scale remains challenging. @minhuanli.bsky.social and I present ROCKET🚀: an AlphaFold augmentation that integrates crystallographic and cryoEM/ET data with room for more! 1/14.

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Brian Liau @brianliau.bsky.social · 12/02/2025

Today in @nature.com we share our back-to-back stories with Ning Zheng’s lab revealing chemical-genetic convergence between a molecular glue degrader & E3 ligase cancer mutations. 1/5

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Vice Mayor Burhan Azeem @burhanazeem.bsky.social · 11/02/2025

I can’t believe it - after years of advocacy, exclusionary zoning has ended in Cambridge. We just passed the single most comprehensive rezoning in the US—legalizing multifamily housing up to 6 stories citywide in a Paris style Here’s the details 🧵

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Sam Berry @sberry.bsky.social · 01/12/2024

I wrote 50,000 words in November! Of course, leave it to me to do my first NaNoWriMo in 15+ years of writing fiction when I'm supposed to be writing my thesis, not a novel... 🤔

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Sam Berry @sberry.bsky.social · 16/11/2024

It feels like there’s some magic spice our best models are missing out on. Preorganization of the binding site seems like one huge thing that can get you from 0/100 to 1/100, but I’m super curious what else is out there to learn

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Sam Berry @sberry.bsky.social · 16/11/2024

This work seems like a big advance in enzyme design, but it’s still fascinating that we can design new proteins that fold with ~90% accuracy, but even with careful biochemical design, DFT, and heaps of machine learning you only get about 1/100 designs with the activity level of natural enzymes!

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