Bryan Dickinson
@chembiobryan.bsky.social
chemical/synthetic biologist, Luddite trying to find better ways to make molecules that do important stuff, dad, @uchicago professor of chemistry
http://www.dickinsonlab.uchicago.edu/
http://www.dickinsonlab.uchicago.edu/
Yes - bluetorial is definitely better =)
November 20, 2025 at 3:48 PM
Yes - bluetorial is definitely better =)
Finally, this was the thesis project of an undergraduate(!!), Josh, now a grad student at Harvard, in close collaboration with our rockstar postdoc, Matt. We also worked with our amazing collaborators at Argonne to get structural data. Awesome team effort!
bsky.app/profile/chem...
bsky.app/profile/chem...
So proud of our undergrad Josh Pixley defending his senior thesis @uchicagopme.bsky.social @uchichemistry.bsky.social today. So much energy and passion. I do hope our world capitalizes on the potential of Josh and all the other developing young scientists.
November 19, 2025 at 6:10 PM
Finally, this was the thesis project of an undergraduate(!!), Josh, now a grad student at Harvard, in close collaboration with our rockstar postdoc, Matt. We also worked with our amazing collaborators at Argonne to get structural data. Awesome team effort!
bsky.app/profile/chem...
bsky.app/profile/chem...
This work can impact drug discovery, diagnostics, and understanding basic molecular recognition. More broadly, it fits into our broader mission to revolutionize the molecular design process. 17/n
November 19, 2025 at 6:10 PM
This work can impact drug discovery, diagnostics, and understanding basic molecular recognition. More broadly, it fits into our broader mission to revolutionize the molecular design process. 17/n
The Bottom Line: Specificity - not affinity - is often the hardest protein engineering challenge. Traditional methods for developing specific binders can take months – and often fail. PANCS-spec-Binders delivers results in DAYS and they really work. 16/n
November 19, 2025 at 6:10 PM
The Bottom Line: Specificity - not affinity - is often the hardest protein engineering challenge. Traditional methods for developing specific binders can take months – and often fail. PANCS-spec-Binders delivers results in DAYS and they really work. 16/n
And it worked! Now we have binders that use a secondary hot spot, but that is LC3B selective. This demonstrates the system can target specific epitopes/regions within a single protein - precision at the molecular level! 15/n
November 19, 2025 at 6:10 PM
And it worked! Now we have binders that use a secondary hot spot, but that is LC3B selective. This demonstrates the system can target specific epitopes/regions within a single protein - precision at the molecular level! 15/n
So… we used PANCS-Spec-binders to force the selections to find binders that bind the next hottest hot spot on LC3B that IS NOT the LIR motif. This is an “Epitope-specific” selection. 14/n
November 19, 2025 at 6:10 PM
So… we used PANCS-Spec-binders to force the selections to find binders that bind the next hottest hot spot on LC3B that IS NOT the LIR motif. This is an “Epitope-specific” selection. 14/n
We figured out this is because the LC3B binders decided to bind at the “LIR motif”, which is shared between GABARAP and LC3B (side note, the LC3B binders were inherently selective – so interesting!). 13/n
November 19, 2025 at 6:10 PM
We figured out this is because the LC3B binders decided to bind at the “LIR motif”, which is shared between GABARAP and LC3B (side note, the LC3B binders were inherently selective – so interesting!). 13/n
Proof of Concept #2 - LC3B Region Targeting: As a second example, we developed binders specific to the LIR (LC3 Interacting Region) of LC3B. This stemmed from our initial PANCS-binder paper, where all our binders were incredibly selective…except for one. Our LC3B binder also bound GABARAP. =( 12/n
November 19, 2025 at 6:10 PM
Proof of Concept #2 - LC3B Region Targeting: As a second example, we developed binders specific to the LIR (LC3 Interacting Region) of LC3B. This stemmed from our initial PANCS-binder paper, where all our binders were incredibly selective…except for one. Our LC3B binder also bound GABARAP. =( 12/n
Swapping this since amino acid between HRas and KRas completely inverts the specificity! Not what we would have guessed, but that is the power of unbiased discovery. 11/n
November 19, 2025 at 6:10 PM
Swapping this since amino acid between HRas and KRas completely inverts the specificity! Not what we would have guessed, but that is the power of unbiased discovery. 11/n
…BUT! The new HRas-selective binders are a total surprise. Through extensive mapping studies, we were ultimately able to pin down the specificity change to a SINGLE AMINO ACID near the tail of the protein. 10/n
November 19, 2025 at 6:10 PM
…BUT! The new HRas-selective binders are a total surprise. Through extensive mapping studies, we were ultimately able to pin down the specificity change to a SINGLE AMINO ACID near the tail of the protein. 10/n
How do out binders bind HRas selectively? Mapping the binding modes of our initial non-isoform selective was relatively easy. Alphafold predicted the site of binding, which we confirmed biochemically and by a really nice X-ray structure…9/n
November 19, 2025 at 6:10 PM
How do out binders bind HRas selectively? Mapping the binding modes of our initial non-isoform selective was relatively easy. Alphafold predicted the site of binding, which we confirmed biochemically and by a really nice X-ray structure…9/n
Proof of Concept #1 - RAS Specificity: In our initial PANCS-Binders paper, the binders we got that bound HRas also bind KRas (like N-LHY). This makes sense, since they are almost identical and share a key hotspot. Now, we can create binders like N-WYN that specifically bind HRAS! 8/n
November 19, 2025 at 6:10 PM
Proof of Concept #1 - RAS Specificity: In our initial PANCS-Binders paper, the binders we got that bound HRas also bind KRas (like N-LHY). This makes sense, since they are almost identical and share a key hotspot. Now, we can create binders like N-WYN that specifically bind HRAS! 8/n
Think of it as training an AI with both good and bad examples - the binders learn what TO bind and what NOT to bind simultaneously. However, unlike AI – which is slow, computationally expensive, and error-prone – PANCS-spec-Binders delivers real results in days. 7/n
November 19, 2025 at 6:10 PM
Think of it as training an AI with both good and bad examples - the binders learn what TO bind and what NOT to bind simultaneously. However, unlike AI – which is slow, computationally expensive, and error-prone – PANCS-spec-Binders delivers real results in days. 7/n
How It Works: The system uses iterative rounds of simultaneous positive selection (bind your target) AND negative selection (avoid similar proteins). 6/n
November 19, 2025 at 6:10 PM
How It Works: The system uses iterative rounds of simultaneous positive selection (bind your target) AND negative selection (avoid similar proteins). 6/n
Why This Matters: Many proteins share "hot spots" - common binding surfaces that make specific targeting nearly impossible. This is especially problematic for protein families like RAS (crucial in cancer), where isoforms are >90% identical but have distinct biological roles. 5/n
November 19, 2025 at 6:10 PM
Why This Matters: Many proteins share "hot spots" - common binding surfaces that make specific targeting nearly impossible. This is especially problematic for protein families like RAS (crucial in cancer), where isoforms are >90% identical but have distinct biological roles. 5/n
The "spec" stands for specificity - finding binders that can distinguish between nearly identical protein family members or even different regions of the same protein! 4/n
November 19, 2025 at 6:10 PM
The "spec" stands for specificity - finding binders that can distinguish between nearly identical protein family members or even different regions of the same protein! 4/n
What is PANCS-spec-Binders? It's a phage-assisted non-continuous selection system that rapidly generates ultra-specific protein binders. It builds on our PANCS-Binders platform from this summer.
www.nature.com/articles/s41...
3/n
www.nature.com/articles/s41...
3/n
PANCS-Binders: a rapid, high-throughput binder discovery platform - Nature Methods
Phage-assisted noncontinuous selection of protein binders (PANCS-Binders) allows multiple high-diversity protein libraries to each be screened against a panel of dozens of targets for high-throughput ...
www.nature.com
November 19, 2025 at 6:10 PM
What is PANCS-spec-Binders? It's a phage-assisted non-continuous selection system that rapidly generates ultra-specific protein binders. It builds on our PANCS-Binders platform from this summer.
www.nature.com/articles/s41...
3/n
www.nature.com/articles/s41...
3/n
The Problem: Protein binders are crucial research tools, but they often suffer from promiscuous binding - hitting multiple similar proteins when you only want ONE specific target. Or, binding your protein, but at the wrong site. Enter: PANCS-spec-Binders! 2/n
November 19, 2025 at 6:10 PM
The Problem: Protein binders are crucial research tools, but they often suffer from promiscuous binding - hitting multiple similar proteins when you only want ONE specific target. Or, binding your protein, but at the wrong site. Enter: PANCS-spec-Binders! 2/n
Reposted by Bryan Dickinson
Dude - it’s like 1/3 of my lab now. The methylcyclopropyl ester is fantastic.
November 11, 2025 at 6:22 PM
Dude - it’s like 1/3 of my lab now. The methylcyclopropyl ester is fantastic.
I ran out of space and there are too many stars to list... Mi Hee Lim, Allie Obermeyer, Chu Wang.... read the website and tag people here if they are on bluesky. I can't wait to attend. If you have never been, Heidelberg in September is lovely. Come hang out and send your students and postdocs!
November 11, 2025 at 5:46 PM
I ran out of space and there are too many stars to list... Mi Hee Lim, Allie Obermeyer, Chu Wang.... read the website and tag people here if they are on bluesky. I can't wait to attend. If you have never been, Heidelberg in September is lovely. Come hang out and send your students and postdocs!