“What fascinated me was the fact that you could potentially predict which molecule could have this effect using thermodynamic principles in silica” www.fiercebiotech.com/special-repo...

"We discovered a TfR1-targeted brain shuttle, check out the brain uptake" (Crook et al. 2020, doi.org/10.1016/j.jm...). "This radioligand does not efficiently cross the blood-brain barrier" (Lin et al. 2025, doi.org/10.1007/s002...)

When will a generative model pass the "Internet Turing Test"? That is, a test subject cannot distinguish an AI-generated internet from the real internet.

Scientists: answering the questions we were dying to know, but too afraid to ask

There's a form of "Personal Computer" Stockholm syndrome where an accumulation of weird tech issues makes computer use border on torture, with a surprising user tolerance threshold. Usually it's only identified by a 3rd party using your machine and remarking... "How the heck do you use this thing?"

"The Illiad" is kinda like "Three-Body Problem" in that their both about vengeful omnipresent beings fucking around with physics on earth.

Sequence logo's are so underutilized, even in protein design papers. Mainly because all the libraries to create them have zero imagination for applications. Represent ensembles of any residue-level property with symbol/color, or use pos/neg enrichment to show differential bias between any two sets!

Grant me the confidence of a scientist asking for help installing software in the Boltz2 webinar Zoom chat

Increasingly convinced there's collusion in "big spinach" to sell washed leaves "wet" in grocery store tubs to accelerate rot and increase sales 🤫🥬💧🤑

leetspeak still alive in the bioinformatics community, academic.oup.com/nar/advance-...

Kinda like mining bitcoin

Love and respect the four-digit PDB code convention, and will miss it. I like how you can use it to roughly "date" structures. Like, 3J5P as a marker for the start of the cryo-EM membrane protein era in 2013.

As if the big scientific publishers weren't bad enough, they sometimes just take journals offline. "Current Opinion in Drug Discovery & Development" ran from 1998-2010. Owned by Thomson but almost all links are broken with no other hosts (that I can tell), pubmed.ncbi.nlm.nih.gov?term=%22Curr...

Biology is hard example #103342: "Our in vivo screening efforts confirmed the requirement for high-affinity binding of the ligand for the cognate receptor to achieve robust activity" (*whisper* R^2 of 0.14) academic.oup.com/nar/article/...

Pharma: "Drug discovery is so hard, we have great binders but they fail in preclinical and clinical research" AI Drug Discovery companies: "So... if we make better binders all diseases will be cured?"

Oral-B Pro 1000 and Philips Sonicare 4100 are the canonical "best electric toothbrushes", but they are really different UX. Philips brush size and vibration is so small it's basically regular brushing with a buzz, but with the Oral-B its truly elevated brushing on easy mode (not a paid advert!)

Academic in Bio ML: "Oh rats, my inverse design sequence recovery metric is really poor on this complex... better lower the temperature." Biotech patent: "In some embodiments, our claim is the endogenous ligand and anything over 20% identity. Trust me look at all these sequences we generated."

In the zone. Completely in sync with the universe. Measured the same weight on my digital scale 3 days in a row. That's even harder than losing or gaining weight 👏👏

How many yogurt lid related cuts go unreported each year due to shame/disgrace? Destigmatize yogurt lid related injury and hold the diary industry accountable.

It's probably been said before, but random Reddit comments with like 1 upvote have a lot of power for specific recommendations. For example, trip planning: city A vs B, or hotel A vs B. Is there any better source of "truth" than these anecdotes? They can rank high on search, pretty empowering...

"I'll be candid: by now you know I care about you personally, but I need to challenge you directly so my behavior doesn't come across as ruinously empathetic or obnoxiously aggressive. Really, it's the only way I can give you feedback so I can sincerely manipulate. Do you have any feedback on that?"

Okay, so it's almost a year after AF3 reported ~75% accuracy on structural prediction of glycosylation. What's the status update on predicting the glycosylated structural proteome?

"Our founding team has combined experience of 20K A100 GPU years"

Excellent study on peptide discovery and characterization, but I was not expecting the computational heavy-lifting of their prediction methodology to be... regex 😜 github.com/Svensson-Lab...

The art of writing a high impact manuscript, github.com/RosettaCommo...

In the VantAI webinar on Boltz-1 the authors describe challenges of arbitrary depositor-defined protein assemblies. Headaches incoming when they discover assembly is also dependent on experimental conditions 😅 E.g. www.biorxiv.org/content/10.1...

Academics may not appreciate the impact of licensing ML models/weights non-commercial use. I've *not* experimentally tested thousands of data points from predictive models because of it. Probably impossible, but there should be a license that requires anonymized validation data to flow to authors.

Ajinomoto Co doing flavour R&D on a whole other level...

How do you scramble a peptide binder? Not by randomly scrambling the sequence! Must account for binding motifs (can have gaps), physicochemical similarity, structure, sequence complexity, chemical identity (like NCAA anchor residues). Chirality-swapped retro-inversions are not a silver bullet...

The field needs a benchmark for benchmarking datasets that ensures collections of data have high scores for data relevance, diversity, quality, and standardization, balanced splits, data annotation, reproducibility, and evaluation metrics; otherwise we're in for "yet another"...

ChatGPT: "Conformational monism" denotes a belief system or viewpoint that a given protein sequence has only one definitive, biologically relevant 3D conformation. Ex. The researcher remained a conformational monist, insisting that their AlphaFold2 model was sufficient to explain structure-function.

Brain shuttle peptide literature is like "the mechanism is through specific receptor targeting and receptor-mediated endocytosis" yet... both T7 and Angiopep-2 function in both L- and D- forms. What's up with that? pubs.acs.org/doi/10.1021/...

First-gen LLMs: hallucinated text, made-up citations Retrieval-augmented generation equipped LLMs: generic summary text with linked documents Next-gen LLMs: reasoning tokens (hidden) with ranked documents (a.k.a. gone full-circle back to web search)

Let's be real here. Quantum computing had no impact here, and even if it did, it's entirely obfuscated by the complexity of the pipeline. Appreciate the authors reported their algorithms running on classical simulators surpassed quantum hardware, even if on proprietary metrics (no one can verify)

Classic general audience slide from David Baker (here, from his Nobel Prize talk). Would love to remake it to visualize the number of known folds for a 100-residue sequence, an estimate of possible folds (w/ sec. structure), and the number of disordered folds (no sec struct). Even more jaw-dropping?

Me on project day #1, harvesting 15 data points from 10 different papers/patents dating back to 1983 and presenting that to the ML team:

Is protein model quality assessment ranking is an outdated problem? Hardly any CASP16 competitors in estimating model accuracy of complexes, and the best methods were from structure prediction teams. Is there really a distinct class of methods that should trade-off interface accuracy over global?

Love it when peptides get publicity as PPI modulators but have stapled peptides really "worked" for undruggable targets? Eager for "Parabilis Medicines" (formerly FOG Pharma) to demonstrate this works in the clinic...

Valuable structure-function study of this receptor. A little pet peeve: "a structure was not available when our experimental work was carried out, so we used AlphaFold2 [...]". Fine, but no comparative figures or analysis outside of saying "it was consistent", no AFm version, PDBs couldn't hurt...

Q: What did Santa say to all the cell biologists on his nice list? A: “CHO-CHO-CHO—Merry Christmas to all, and may your yields be bright!”

Is there any UX more frustrating than being forced to scroll through a multi-page document while holding a dragged object you want to drop? Seconds feel like hours as pages move through molasses while you hopelessly scrub the page's edge in hopes of accelerating scroll speed to end the misery...

"We're proud to release a state-of-the-art protein ML model!" [extensive thread of benchmarking and validation]. "In conclusion, please look out for version 2, this model is old and busted"

I'm a big fan of this database of peptide-drug conjugates. It's a miracle they were able to consolidate chemical rep. and experiments for PDCs across stages (the majority are not on ChEMBL); but they're still missing monomer descriptions of PDCs (i.e. HELM representation)... doi.org/10.1093/nar/...

Truth is stranger than fiction, in this case in the spirit of Willy Wonka. "Yes, on your left you'll see the sugar-coated peptide spaghetti lotus pond".

Every step forward in drug development is a victory in the battle against disease. Concept art for the boardroom of our future office. I just don't think we'll be able to secure lab space with an appropriate underground bunker...

Murphy's Law of Molecular Dynamics Simulations: "If there's a rare event you want to sample, all other rare events will be sampled first".

Just a general PSA that getting a COVID booster before travelling is a great idea to avoid bringing back unwanted "biological souvenirs"...

Perfectly normal sentence in computational biology: "The PMF of mutations in mitochondrial ATP synthase in cancer highlight potential sites which impact the PMF, which we studied computationally using a PMF."

There was nothing human about this particular green-over-chrome construct. Kassad noted the two horn-shaped ears, simple tunic, the profusion of thornspikes on the body, but not once did his gaze leave the two thousand-faceted eyes. "The Shrek", thought Kassad. "The Lord of Pain", whispered Moneta.

Fantastic review, but it's sad computational progress is so slow in this space. Outlook still positive, "Allied advances in computational de novo protein design will provide novel synthetic scaffolds and elucidate proteomimetic structures capable of disrupting previously intractable interactions."