C-GEM, the NSF Center for Genetically Encoded Materials

Co-Translational Incorporation of (R)- and (S)-β2-Hydroxyacids In Vivo: Directed Evolution of Efficient Aminoacyl-tRNA Synthetases Expanding the genetic code of living cells with noncanonical monomers (ncMs) relies on engineered aminoacyl-tRNA synthetases (aaRS) and their cognate tRNAs. Conventional aaRS engineering strategies rely on translation-dependent selection systems, limiting their utility for ncMs that are poorly accommodated by the native translational machinery. To address this limitation, we recently developed START, a translation-independent platform that selects Methanomethylophilus alvus pyrrolysyl-synthetase (MaPylRS) mutants based on their ability to acylate cognate tRNAMaPyl. START uses barcoded tRNAs to encode the identity of distinct aaRS mutants in a library. Acylation by active aaRS mutants protects the corresponding tRNAs from periodate oxidation, and their identity is retrieved subsequently through sequencing. START was previously applied to genetically encode noncanonical α-amino acids. Here, we successfully applied START to engineer MaPylRS mutants capable of acylating tRNAMaPyl with diverse non-α-amino acid substrates with good efficiency and fidelity, including (R) and (S) enantiomers of a β2-hydroxy acid, a β2-amino acids, and a malonate. Several mutants exhibit notable polyspecificity across noncanonical backbones while maintaining selectivity against their α-amino acid counterparts. Using these novel enzymes, we demonstrate the ribosomal incorporation of both (R)- and (S)-β2-hydroxy acids into a luciferase reporter protein expressed in Escherichia coli with good efficiency and fidelity. These results imply that highly active engineered aaRS/tRNA pairs can overcome the recently established limitations of EF-Tu with respect to non-α-amino acid substrates. The engineered MaPylRS mutants also enabled the successful incorporation of both (R)- and (S)-β2-hydroxy acids into a protein expressed in mammalian cells, demonstrating for the first time that eukaryotic translation can accommodate non-α-backbones.

Chintan's work demonstrating the efficient incorporation of non-α-amino acid backbones into proteins expressed in both E. coli and mammalian cells just came out! A great collaborative effort from @cgemcci.bsky.social! pubs.acs.org/doi/10.1021/...

New paper alert 🚨 from @cgemcci.bsky.social showing high-resolution cryo-EM structures and mass spectrometry data that help us understand how beta-hydroxy acids are accommodated and incorporated by the ribosome!

Flyer advertising the C-CAS Summer Undergraduate Research Fellowship Program Program Details: Students awarded a fellowship will conduct their cutting-edge research on topics of organic synthesis, computational chemistry, and artificial intelligence and machine learning (AI/ML). These students will be placed in the lab of a C-CAS faculty advisor at one our the seventeen partner universities and work closely with a PhD student or postdoctoral researcher as their immediate mentor. Applications Due January 30, 2026

C-CAS is now accepting applications for the 2026 Summer Undergraduate Research Fellowship (SURF) Program.

More details here: ccas.nd.edu/outreach/sur...

#chemistry #computerscience #chemsky #summerresearch #REU #undergraduateresearch

Headshots of Veronika, Jill, and Alanna

Out today in Science Magazine — First author Veronika Kivenson and PIs Jill Banfield (The Banfield Lab) and Alanna Schepartz team up to reveal a new genetic code in #archaea, with implications for #methane and #climate, and #bioengineering! Learn more: https://ow.ly/Kuem50Xurh0

Site-selective protein editing by backbone extension acyl rearrangements - Nature Chemical Biology A post-translational backbone extension acyl rearrangement (BEAR) reaction has now been developed that converts a ribosomal protein product into a new product containing a β-peptide, γ-peptide or δ-pe...

Today, I'm grateful that Alanna Schepartz is visiting Tufts. Alanna's leadership of @cgemcci.bsky.social has led to impressive advances in genetic code expansion, including recently published work pushing encoding beyond alpha-amino acids.

#ChemSky #ChemChat

www.nature.com/articles/s41...

An archaeal genetic code with all TAG codons as pyrrolysine Multiple genetic codes developed during the evolution of eukaryotes and bacteria, yet no alternative genetic code is known for archaea. We used proteomics to confirm our prediction that certain archae...

✨ New paper in Science: An archaeal genetic code with all TAG codons as pyrrolysine.
www.science.org/doi/10.1126/...

A collaboration with @innovativegenomics.bsky.social

Congrats to the Banfield lab, @roeleah.bsky.social , @nxhamlish.bsky.social , and Alanna!
#NSFfunded

Home - Bay Area Science Festival Bring the whole family to experience 100+ jaw-dropping demonstrations, hands-on experiments, astounding games, behind the scenes lab tours, film screenings

🧬 Join C-GEM at this year’s massive Bay Area Science Festival on October 25, 2025 to learn all about proteins and polymer science. This event is free for all—tell your friends!

@bayareascifest.bsky.social
Find out more: www.bayareasciencefestival.org
#ScienceTogether #BayAreaScienceFestival

NSF Graduate Research Fellowship Program (GRFP)

New: After a long wait, the GRFP solicitation is live! Deadlines have been extended to early November, so applicants have a bit over a month to submit. www.nsf.gov/funding/oppo...

Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines - Nature Chemistry Expanding the complexity of genetically encoded peptides is a long-standing challenge at the intersection of chemistry and biology. Now it has been shown that linear peptides with a reactive N-termina...

✨ New paper in Nature Chemistry: Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines
www.nature.com/articles/s41...

Congrats to Isaac, Taylor, Diondra, Cameron, Tamir, Alanna, Scott, and collaborators!

#NSFfunded

cartoon confetti raining down on the Cambridge Science Carnival logo and title. Underneath is text that reads: Sunday, September 21, 12-4pm. The STEAM extravaganza returns to the Kendall/MIT Open Space with hundreds of hands-on activities for the whole family.

🎈 Come visit C-GEM's table to learn about polymer science at the Cambridge Science Carnival on Sunday, September 21, 2025!

Find out more about the free event here: cambridgesciencecarnival.org

Managing Director, NSF Center for the Mechanical Control of Chemistry Job TitleManaging Director, NSF Center for the Mechanical Control of Chemistry Agency Texas A&M University Department Chemistry Proposed Minimum SalaryCommensurate Job LocationCollege Station, Tex...

We’re #hiring! The NSF Center for the Mechanical Control of Chemistry (CMCC) is looking for a Managing Director.

Applications are open until September 5. Learn more and apply here ➡️ tamus.wd1.myworkdayjobs.com/en-US/TAMU_E...

#Recruiting #Jobs

Site-selective protein editing by backbone extension acyl rearrangements - Nature Chemical Biology A post-translational backbone extension acyl rearrangement (BEAR) reaction has now been developed that converts a ribosomal protein product into a new product containing a β-peptide, γ-peptide or δ-pe...

I created a protein backbone editing method and named it after my alma mater (x2)! Out now in Nature ChemBio, we show the first examples of a β2-, γ-, and δ-amino acid encoded into full length proteins expressed in cells. www.nature.com/articles/s41...

Site-selective protein editing by backbone extension acyl rearrangements - Nature Chemical Biology A post-translational backbone extension acyl rearrangement (BEAR) reaction has now been developed that converts a ribosomal protein product into a new product containing a β-peptide, γ-peptide or δ-pe...

✨New in Nat Chem Biol: Site-selective protein editing by backbone extension acyl rearrangements
bit.ly/4oKQ251

Congrats @roeleah.bsky.social, Izzi, Carly, Taylor, Bhavana, @nxhamlish.bsky.social, Arjun, Diondra, Zhongqi, @achemsynbio.bsky.social, Matt, Scott, Alanna, and collaborators!
#NSFfunded

We’re excited to announce that the NSF renewed C-GEM’s funding for Phase IIb! Thank you to all of our researchers for their hard work over the past five years 🎊

chemistry.berkeley.edu/news/nsf-com...
#NSFfunded @berkeleychemistry.bsky.social

Learn about Directed Evolution Through Play, Center for Genetically Encoded Materials C-GEM transformed the Nobel Prize-winning technique of directed evolution into an educational board game! Directed Evolution: The Game tasks players with...

Have you ever wondered how scientists use evolution to engineer proteins? Find out with C-GEM’s new board game—Directed Evolution: The Game!

Download to play it at home: gem-net.net/learn-about-...

Further Confirmation of the Structure of 3′-(2-Pyridyldithio)-3′-deoxyadenosine and 3′-Thio-3′-deoxyadenosine: Synthetic Convergence with Cordycepin 3′-Deoxynucleosides have demonstrated profound biochemical utility, including in our recent work on the use of aminoacyl thio-tRNAs for in vitro translation. Though our preparation of 3′-(2-pyridyldithio)-3′-deoxyadenosine─a key synthetic precursor en route to aminoacyl thio-tRNAs─followed robust prior precedents, an unrelated recent structural revision prompted us to validate the regioselectivity of our route further. Here we provide confirmatory evidence for the structure of 3′-(2-pyridyldithio)-3′-deoxyadenosine and downstream analogues via synthetic convergence with a 3′-deoxynucleoside antibiotic, cordycepin, and concomitant MicroED analysis.

✨ New from C-GEM in JOC @pubs.acs.org:

Further Confirmation of the Structure of 3′-(2-Pyridyldithio)-3′-deoxyadenosine and 3′-Thio-3′-deoxyadenosine: Synthetic Convergence with Cordycepin

Congrats to Taylor and coauthors! #NSFfunded
pubs.acs.org/doi/10.1021/...

#NSFfunded #synbio

Escherichia coli ribosomes support translation of (R) and (S) β2-hydroxyacids in vitro: a structural and biochemical study The ribosomal incorporation of backbone-modified amino acid analogs into peptides and proteins enables the programmed synthesis of sequence-defined biopolymers with tunable properties. However, the su...

✨ New C-GEM preprint
E. coli ribosomes support translation of (R) and (S) β2-hydroxyacids in vitro: a structural and biochemical study

Congrats @c-majumdar.bsky.social, @alexandra-kent.bsky.social, @nxhamlish.bsky.social, Cathy, Katie, Alanna, and @jhdcate.bsky.social!
chemrxiv.org/engage/chemr...

Monitoring monomer-specific acyl–tRNA levels in cells with PARTI Abstract. We describe a new assay that reports directly on the acylation state of a user-chosen transfer RNA (tRNA) in cells. We call this assay 3-Prime Ad

✨ New C-GEM Breakthrough Article in
@narjournal.bsky.social

Monitoring monomer-specific acyl–tRNA levels in cells with PARTI

Congratulations to Meghan, @carlyschissel.bsky.social, Izzy, Cameron, and Alanna!

academic.oup.com/nar/article/...

🎉 To celebrate the 75th anniversary of the NSF, the Centers for Chemical Innovation collected thank-you notes from our members that highlight the positive impact of NSF support.

Read the notes here ➡️ nsfcci.org/nsf75

#NSF75 #ThankYou #CCI #CMCC

C-CAS would like to wish the NSF a happy 75th birthday! Thank you for all you do for us and for science.

#NSF #NSF75 #CCAS #chemsky #chemistry

A header in gold and silver text that reads "NSF 75 years of discovery & innovation" Below that is an open envelope with a piece of paper sticking out. On the paper in a handwritten font reads, "Thank you, NSF!" and below the text are the logos of the following NSF centers: C-CAS, CSN, CSOE, MONET, CSP, CMCC, and C-GEM.

🎉 To celebrate the 75th anniversary of the NSF, the Centers for Chemical Innovation collected thank-you notes from our members that highlight the positive impact of NSF support.

🎈 Read the thank-you notes here: www.nsfcci.org/nsf75

#NSFfunded

🚨 New PARTI trick: NAR #Breakthrough article from cgemcci.bsky.social describes a new technique for studying tRNA acylation 🚨

👉 Introducing '3-Prime Adenosine-Retaining Aminoacyl–tRNA Isolation (PARTI)'.

📖 Read the full article here: doi.org/10.1093/nar/...

#tRNA #Translation - Part 1

Monitoring monomer-specific acyl–tRNA levels in cells with PARTI Abstract. We describe a new assay that reports directly on the acylation state of a user-chosen transfer RNA (tRNA) in cells. We call this assay 3-Prime Ad

✨ New C-GEM Breakthrough Article in @narjournal.bsky.social

Monitoring monomer-specific acyl–tRNA levels in cells with PARTI

Congratulations to Meghan, @carlyschissel.bsky.social, Izzy, Cameron, and Alanna!

academic.oup.com/nar/article/...

STEM Day Join The Lawrence for one of our signature Five Dollar Days as we commemorate the 75th anniversary of the National…

🎂 We’re celebrating the NSF’s 75th birthday on Saturday, May 10 with our friends at the Lawerence Hall of Science 🎈

Join us at STEM Day and learn about C-GEM's next generation biopolymers!

A shuttle will be available from Downtown Berkeley BART.

lawrencehallofscience.org/events/stem-...

We're honored that our FRSA structure contributed (in a tiny way) to this amazing milestone! www.rcsb.org/structure/7U0R

Flyer for the 2025 Next Generation Faculty Symposium (including QR code in top right corner). This symposium highlights the work of exceptional early-career scientists in the broad field of quantitative biological and biomedical sciences, with a track record of excellence in research, leadership, mentorship, and community engagement. These early career scientists are preparing to launch a faculty search. Applications are due May 30th, 2025.

Hello Community!
Are you a postdoc/grad student preparing to launch a faculty search? Do you have a track record of excellence in research, leadership, mentorship & community engagement? Apply to the 2025 Next Generation Faculty Symposium: www.berkeleystanfordnextgensymposium.com! Pls repost! (1/3)

Two states of an RNA switch using malachite green as a reporter.

Are you a biochem professor attending the ASBMB annual meeting in April? @sarahsmaga.bsky.social and I will be leading a workshop on using the Eterna platform to introduce RNA pairing and folding in the undergraduate classroom: events.rdmobile.com/Sessions/Det...

Hope to see you there! 🧬