Sam Berry

Sam Berry

@sberry.bsky.social

Harvard Biophysics PhD candidate studying protein evolution with a focus on transporters in the Gaudet and Marks labs. Occasional fiction writer. Proud cat dad.

1.1K followers718 following25 posts

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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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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.

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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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:

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...

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.

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+.

Sam Berry reposted

Sam Berry reposted

Replying to @davidho.bsky.social

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.

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!

Harvard_MCB@harvardmcb.bsky.social

Senior MCB, CPB, and Neuroscience Concentrators Receive the Thomas Temple Hoopes and Henderson Prizes #AcademicSky www.mcb.harvard.edu/department/n... @rachellegaudet.bsky.social @naoshigeuchida.bsky.social @neurovenki.bsky.social @dulaclab.bsky.social @rivaselenarivas.bsky.social

Sam Berry reposted

Sam Berry reposted

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.orgZero-shot design of drug-binding proteins via neural selection-expansionComputational 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...

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.comAlphaFold is running out of data — so drug firms are building their own versionThousands 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.

Sam Berry reposted

"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.comOpinion | What Autocrats Want From Academics: ServilityIn 1931, Italian scholars were made to take loyalty oaths. Will that happen to us?

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

Hemant Mehta@friendlyatheist.com

Lol. All the anti-trans, reflexively contrarian, “anti-woke” scientists have contributed to a book about how science is under attack. Somehow, there are no chapters dedicated to how Republicans are decimating research and firing experts.

Sam Berry reposted

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.orgNIH ban on renewing senior scientists adds to assaults on its in-house researchPolicy follows firings of tenure-track scientists and suspension of training programs

Sam Berry reposted

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.

Sam Berry reposted

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 🧵

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... 🤔

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!

Kevin K. Yang 楊凱筌@kevinkaichuang.bsky.social

The Baker lab seems serious about moving into enzyme design. Here, they train a flow-matching model that can be conditioned by atomic coordinates and then use it to design enzymes based on active site geometry specified by density functional theory. www.biorxiv.org/content/10.1...

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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