Diagram titled ‘Protein–Drug Prediction Task Breakdown’ showing a hierarchical tree of modeling tasks. Top branches include apo monomer and protein–protein interactions, with sub-branches such as ensembles, induced-fit models, multimers, folded–unfolded complexes, and protein–ligand complexes with mutation effects on binding. Additional branches include potency, ADMET properties (e.g., solubility and blood–brain barrier penetration), and kinetics (e.g., koff). A legend indicates model maturity levels: solid lines (established), dashed lines (promising), and dotted lines (untapped).

More protein-ligand data are needed for AlphaFold-like models (& AI/ML) to enable prospective design!

Check out our piece in "Current Opinion in Structural Biology" – Equal parts a thank-you-letter to the PDB & summarizes how datasets will enable task-focused models!

Link: doi.org/10.1016/j.sb...

A dark brown dog with a graying muzzle stands on a couch, facing the camera with wide, shiny eyes and its tongue playfully sticking out. The dog wears a collar with tags, and a pink blanket is draped beside it. Soft daylight from a nearby window illuminates the cozy indoor scene.

"Reject doomscrolling. Embrace naptime"

How many STEM Ph.D.s were lost from the U.S. federal government last year?

My colleagues @mghersher.bsky.social and @policyhound.bsky.social dug into a recent data release to find the answer. A @science.org exclusive.

www.science.org/content/arti...

I don't think you non-science people realize what it takes to get a grant funded by NIH. Started experiments in Sept 2021 to generate 3 new mouse mutants to model human disease. Prelim dara shows they have relevant disease phenotypes worthy of study. Need a small grant first to characterize /1

This is more than half the NSF's total annual budget.

New preprint!
How many crystal structures do you need to trust your docking results? It turns out, if you know how your main scaffold binds in the pocket, not that many! Check out this work from recently-defended lab member @keysandcompounds.bsky.social

On BioRxiv:
www.biorxiv.org/content/10.1...

I'm honored to share that I've been selected as a 2026 PhRMA Foundation Predoctoral Fellow in Drug Discovery. This fellowship will support my research assessing how clinically relevant missense mutations impact kinase activity.

Read more about our work here.

Are you a postdoc stuck in the US?! Is your research stalled or are you in any way affected by the whims of that unfettered madman? Interested in MD simulations of large biomolecules?!

Consider joining me at the University of Freiburg!

uni-freiburg.de/frias/call-f...

How many crystal structures do you need to trust your docking results? www.biorxiv.org/content/10.1101/2025.09....

How many crystal structures do you need to trust your docking results?

Figure 2

Figure 3

Figure 4

How many crystal structures do you need to trust your docking results? [new]
Accurate drug docking needs crystal struct. Template docking via mol. similarity helps w/ ltd. data.

International Postdocs From 60 Countries Are Training at MSK in 2025 What inspires the outstanding young scientists who come from around the world to train at MSK?

DYK: 76% of MSK postdoctoral researchers are international, coming from more than 60 countries for training and mentorship that translates into scientific discoveries across the globe? 🌎 Learn more about our incredible MSK postdocs:

#PostdocAppreciationWeek

Sukrit, dressed in a blue and gray suit, is standing in front of the stage at a Naturalization ceremony holding a US flag

On Monday I took my Oath of Allegiance and become a Naturalized US Citizen! Huzzah!

I was thinking like a 3D Celtic Knot more but pretzel is equally valid (and more delicious)

Can't wait to simulate whatever this is 🤔

Simple Method to Optimize the Spacing and Number of Alchemical Intermediates in Expanded Ensemble Free Energy Calculations Alchemical free energy calculations are essential to modern structure-based drug design. Such calculations are usually performed at a series of discrete intermediates along a nonphysical thermodynamic...

Excited to share work now out in #JCIM @acs.org !
doi.org/10.1021/acs....

Alchemical free energy calculations are indispensable in computational drug design. We present an improved approach for optimizing the schedule of alchemical intermediates by minimizing thermodynamic length.

1/7

📢Important announcement! Today, the @asapdiscovery.bsky.social consortium disclosed the structure of our preclinical candidate, ASAP-0017445, a promising broad-spectrum antiviral with potent activity against SARS-CoV2 and other viruses belonging to the same family. (1/10)

This is the moment we've worked toward for a long time: First public disclosure of the @asapdiscovery.bsky.social pan-coronavirus antiviral aiming to help keep humanity safe from future pandemic threats like MERS-CoV and other bat coronaviruses.

Five people, covered in bright Holi powder, stand arm-in-arm in front of a waterfront railing with a cityscape in the background. They’re all smiling and wearing colorful, powder-stained clothes.

Happy Holi, from the @jchodera.bsky.social lab!!

This work is now published in J Phys Chem B! Check out our work showing that simulations predict the impact of distal mutations on kinase-inhibitor binding, and our experimental NanoBRET dataset of 94 kinase mutations that provide a benchmark for future methods. Link:
pubs.acs.org/doi/full/10....

How Science Can Adapt to a New Normal Opinion | In the wake of attacks on the research enterprise, scientists need to focus on protecting its fragile infrastructure.

"No one is coming out of the sky to give you your grant money. Your citation portfolio won’t survive this market crash. Your credentials mean nothing. Everything is going to change."

New for @undark.org

undark.org/2025/03/06/o...

NIH operates three cycles of grant review, approval for funding, and actual notice of award

right now all three cycles are blocked

if noncompeting awards are frozen, that's a fourth block

American science is running out of oxygen because of an acute airway obstruction

Composite image illustrating enzyme inhibition concepts with a black dog in different poses: Top-left: The dog wears a pink flying disc on its head, labeled “Non-competitive (allosteric) inhibition (E–Inc).” Center: The dog in a tub, tongue out, labeled “E,” connected to “E–S” (enzyme–substrate). Top-right: The dog holding a yellow tennis ball, labeled “Competitive inhibition (E–Ic).” Bottom-center: The dog chewing a blue ball, labeled “Substrate binding.” Arrows and labels show the relationships between each form of the enzyme.

Composite image demonstrating “good” versus “bad” enzyme–substrate binding with the same black dog: Left: The dog with a blue ball in its mouth, labeled “E–Sᵍ” (“bad” binding mode). Center-left: The dog in a tub with tongue out, labeled “E.” Center-right: The dog holding a blue ball in a more controlled way, labeled “E–S” (“good” binding mode). Far right: The dog beside shredded toy pieces, labeled “E + P” (product formation). Text labels and arrows illustrate the transition from enzyme–substrate complexes to products.

It's important to communicate to the public the importance of basic science. Coco is happy to help explain drug binding mechanisms and enzyme kinetics basics:
#scicomm

2025 Study section tracking

Wondering if your study section cancelled? I update this sheet daily. As of today, 56/124 study sections that should have met since Jan 2, 2025 have "not met as scheduled." docs.google.com/spreadsheets...

2025 Federal Financial Assistance Freeze On Monday, January 27th, 2025, President Trump issued an order to freeze virtually all of approved and legally required federal funding.

Please share:
@delauro.house.gov is cochair of the US House Congressional Rapid Response Task Force and Litigation Working Group.

They are looking for instances where the impoundment and restriction of NIH/NSF funds is having a negative impact. Submit examples here delauro.house.gov/constituent-...

In Early-Phase Pancreatic Cancer Clinical Trial, Investigational mRNA Vaccine Induces Sustained Immune Activity in Small Patient Group Learn how MSK researchers are deploying mRNA vaccines against pancreatic cancer.

An #NIH-funded research team has developed an mRNA vaccine to treat pancreatic cancer. Results from the clinical trial were published this week in Nature.

#pancreas #cancer #mRNA #vaccine #medsky #science #medicine #bluesky

Graduate admissions being put on hold because of the chaos...

Excited to share what I’ve been working on with @tkaraletsos.bsky.social to transform the field of drug discovery with atomistic foundation simulation models!

I could not be more thrilled to be working with this dream team.

achira.ai

We are hiring a Flatiron Research Fellow in the Structural Molecular Biophysics team! Experience with cryoEM and/or membrane protein simulations are a plus! Happy to chat in person with anyone at #bps2025 ! apply.interfolio.com/160227

Figure 1 from arXiv preprint https://doi.org/10.1101/2025.01.06.631610 Fig. 1 Espaloma is an end-to-end differentiable molecular mechanics parameter assignment scheme for arbitrary organic molecules. Espaloma (extensible surrogate potential optimized by message-passing) is a modular approach for directly computing molecular mechanics force field parameters FFF from a chemical graph G such as a small molecule or biopolymer via a process that is fully differentiable in the model parameters FNN. In Stage 1, a graph neural network is used to generate continuous latent atom embeddings describing local chemical environments from the chemical graph. In Stage 2, these atom embeddings are transformed into feature vectors that preserve appropriate symmetries for atom, bond, angle, and proper/improper torsion inference via Janossy pooling.54 In Stage 3, molecular mechanics parameters are directly predicted from these feature vectors using feed-forward neural networks. This parameter assignment process is performed once per molecular species, allowing the potential energy to be rapidly computed using standard molecular mechanics or molecular dynamics frameworks thereafter. The collection of parameters FNN describing the espaloma model can be considered as the equivalent complete specification of a traditional molecular mechanics force field such as GAFF38,39/AM1-BCC55,56 in that it encodes the equivalent of traditional typing rules, parameter assignment tables, and even partial charge models. Reproduced from ref. 49 with permission from the Royal Society of Chemistry.

Everything is chaos, but I wanted to share some awesome recent science from the lab that hints at where the future of biomolecular simulation is headed:

Foundation simulation models that can be fine-tuned to experimental free energy data to produce systematically more accurate predictions.