Sarah Rauscher

Structures from AlphaFold3 - while often impressively good - tend to fail representing the dynamic ensembles accurately. And often parts of the structure are not correct. Adding experimental data, directly in AlphaFold's diffusion step, provides physically realistic protein ensembles. This image shows two cases where AlphaFold3-only structures were largely improved by guiding with experimental data.

📢 New preprint:
Experiment-guided AlphaFold3 resolves accurate protein ensembles.
doi.org/10.1101/2025...

AlphaFold3 is incredible, but has crucial limitations: it typically collapses to a single conformation, ignoring the inherent dynamics of proteins. And it can be wrong. Here's a solution. 🧵👇

Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release - Nature Communications Distal mutations, though far from the active site, enhance Kemp eliminase catalysis by tuning conformational dynamics that facilitate substrate binding and product release, thereby promoting the full catalytic cycle.

Thrilled to share that our latest article is now out in final form! A great collaboration with @fraserlab.com and @silviaosuna.bsky.social.

Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release

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

New IDPSeminars season on deck 🤩

We hope you can join us to learn about some exciting science!

More info in the post below👇

📢 New preprint: Aromatic Ring Flips Reveal Reshaping of Protein Dynamics in Crystals and Complexes.

We addressed a long-standing question that people debated already in the 1970s - but it still remained open:
Do proteins in crystals move as they do in solution? We used ring flips to find out.
1/n

We are thrilled to be part of Project Diffuse, building infrastructure for the dynamic future of structural biology.

We are helping to lead the modeling and encoding efforts of this project, including designing infrastructure that allows AI to learn from the full complexity of experimental data.

Hi bluesky scientists! Recently, @stephanieaw.bsky.social @fraserlab.com held a workshop at UCSF to discuss methods for modeling heterogeneity in structural biology (conformationalensembles.github.io).

Very happy that this story found its home at @pnas.org

www.pnas.org/doi/10.1073/...

The Tortured Proteins Department Esp. 2 with @fraserlab.bsky.social is out! In addition to bantering about the craziness of the times, we chat about some recent exciting preprints (see links below).

open.spotify.com/show/10PHVou...

Advances in uncovering the mechanisms of macromolecular conformational entropy - Nature Chemical Biology Protein conformational entropy plays a vital role in functions like binding and catalysis. This Perspective discusses three ways macromolecules use conformational entropy: prepaying entropic costs, re...

A Perspective by @stephanieaw.bsky.social and @fraserlab.com discusses ways macromolecules use conformational entropy to control binding, catalysis, and allostery

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

I am glad that this profile written by Luc Rinaldi for Toronto Life Magazine is out. It is about what I am doing and where I am going. Thanks to Luc for the time he took to write this piece. #chemsky #compchemsky

Postdoctoral Research Associate - Physics Position Summary The GrandPre group in the Department of Physics at WashU in St. Louis invites applications for a theoretical/computational postdoctoral position, with an anticipated start date around...

Hello Everyone, I’m following up to share the job advertisement for a postdoctoral position in my theory/computational group, starting this fall. The position will focus on non-equilibrium biophysics and soft matter.

The job ad is here: wustl.wd1.myworkdayjobs.com/en-US/Extern....

Looking forward to this workshop on Macromolecular Conformational Ensembles in June!

💭 Would you like to contribute to projects in the field of "Theory and Methods for Non-equilibrium #Theory and Atomistic Simulations of Complex# Biomolecules"? Join our department as #PhD student or #Postdoc at @mpi-nat.bsky.social in 🇩🇪 🔗 Here are more details www.mpinat.mpg.de/4965656/10-2... #job

✨ Check out @mackevinbraza.bsky.social 's new work on full length APOBEC3B, which shows how the NTD modulates active site opening in the CTD

Collab w/ @adaozlemdemir.bsky.social & Aihara, Herzik, & Harris labs

pubs.acs.org/doi/10.1021/...

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.

Conformational landscapes of a class I ribonucleotide reductase complex during turnover reveal intrinsic dynamics and asymmetry Nature Communications - Structural dynamics play an essential role in enzymatic catalysis. Here, the authors use cryo-EM to reveal the conformational landscapes of a class I ribonucleotide...

Some happy news from @andolab.bsky.social !! 😀🥳

Ever wonder how protein motions regulate enzyme turnover? Check out this paper by Darren (Da) Xu, et al. that was published today: rdcu.be/edf2A

Direct visualization of electric-field-stimulated ion conduction in a potassium channel Understanding protein function would be facilitated by direct, real-time observation of chemical kinetics in the atomic structure. The selectivity fil…

"The basic principles of selective permeation are well established through a long history of landmark structural and functional studies, providing an excellent basis for validating dynamical features observed using EFX." 🎉💥👏🏻🧪

www.sciencedirect.com/science/arti...

At high concentrations of PEG, we find that mCherry molecules associate to form large aggregates. By carrying out experiments with a bulkier crowder, dextran, we show that the effects of crowder-protein interactions depend on the crowder's chemical features and its bulkiness.

We find that PEG-wrapping around the side chains of lysine residues is prevalent, occurring in at least 20% of all crystal structures containing PEG, which corresponds to approximately 0.4% of all structures in the PDB.

We observe a specific, stable PEG-protein interaction in which PEG molecules wrap around the side chains of surface-exposed lysine residues.

We provide a detailed view of the influence of PEG crowding on the structural equilibrium and the function of a widely used fluorescent protein, mCherry. PEG interacts with the protein non-isotropically, and it is not well-described as a classical excluded volume crowder.

A recent paper, “PEG-mCherry interactions beyond classical macromolecular crowding,” by Liam Haas-Neill from our lab, Khalil Joron and Eitan Lerner @lernerlab.bsky.social is published in Protein Science.
onlinelibrary.wiley.com/doi/full/10....

Come to #accelerate25 the premier conference on #aiformaterials #selfdrivinglabs #chemsky Please RT

Our lab celebrated Ethan Lee's successful PhD defense last week. You can read his recent study on allostery in the main protease of SARS-CoV-2 here: pubs.acs.org/doi/abs/10.1...
Stay tuned for more of his work on IDRs + allostery. Congratulations, Ethan!

Looking forward to #BPS2025 & presenting our collaborative study with @lernerlab.bsky.social on the effects of PEG crowding on the fluorescent protein mCherry. Drop by our poster (Monday, board B4)!

It is almost happening - #BPS2025 - and we are happy to attend and present our research.
A thread.
1) I will give a talk on Saturday morning at the Biological Fluorescence subgroup, presenting the work spearheaded by the PhD student Khalil Joron, about

Proud to share:

"Ensemble docking for intrinsically disordered proteins"

from Dartmouth undergrad Anjali Dhar 24' and grad student Tommy Sisk. We present ensemble docking strategies for IDPs that, remarkably, seem to work!

www.biorxiv.org/content/10.1...

Code: github.com/paulrobustel...

Program Head - Molecular Medicine, The Hospital for Sick Children Research Institute - Toronto (City), Ontario (CA) job with The Hospital for Sick Children (SickKids) Research Institute | 667223 Provide leadership and mentorship to members of the Molecular Medicine Program and influence the scientific direction of the Research Institute

Come be my boss!
We're looking for a new Program Head for the Molecular Medicine Program at the Hospital for Sick Children.
Toronto, Canada
(the deadline has been extended from Jan 31)
Please Re-post.
jobs.sciencecareers.org/job/667223/p...

Martin Karplus, Chemist Who Made Early Computers a Tool, Dies at 94 (Gift Article) Proving skeptics wrong, he shared a Nobel Prize in 2013 for using computers to better understand chemical reactions and biological processes.

Obituary for computational chemistry pioneer Martin Karplus in the New York Times (gift link).
#CompChem #ChemSky 🧪
www.nytimes.com/2025/01/13/s...

📢 Our new paper in #SciAdv on #Bayesian electron density determination from single-molecule #X-ray scattering is out! 🧐 High resolutions can be achieved from #XFEL exp at low S/N ratios using less than 50 #photons per image! 🔗https://www.science.org/doi/10.1126/sciadv.adp4425 @mpi-nat.bsky.social