Ezequiel Galpern

Our method for predicting folding dynamics/mechanisms from sequence info is now a book chapter! link.springer.com/book/9781071...

@diegulise.bsky.social

Applications are open for the @crg_eu PhD Programme! 20 fully funded positions — including one in our group through the Evolutionary Medical Genomics ITN.

Join us to develop deep generative models of cross-species data to tackle open questions in disease genetics.

www.crg.eu/en/content/t...

Google Colab

Dark Energy is not a relative score, but provides a common scale and has physical energy units. And it can be also computed even if ΔΔG is not available, using AWSEM force-field. You can compute it for your favorite PDB colab.research.google.com/github/eagalpern/colabs/blob/main/DarkEnergy.ipynb

Some sites have, on average over all the possible variants, high Dark Energy. In those cases, there is a function beyond protein folding affecting natural selection. This is clearly the case of Enzyme catalytic sites

The idea is simple. For a deleterious mutation, we expect the protein to get destabilized. But how much? Correlations between a ΔΔG DMS and the corresponding ESM-2 scores are not perfect. We define the difference between these two free energies as a ‘Dark Energy’.

Probing the Dark Energy in the Functional Protein Universe We show how to localize and quantify the functional evolutionary constraints on natural proteins. The method compares the perturbations caused by local sequence variants to the energetics of the prote...

❗New Preprint w/ C Bueno (‪@cabb99.bsky.social‬), IE Sánchez (@nachoquique.bsky.social‬), PG Wolynes & DU Ferreiro (@diegulise.bsky.social‬)

We define the Protein Dark Energy and use it to localize and quantify the functional evolutionary constraints on natural proteins

arxiv.org/abs/2508.08109

Google Colab

And you can make folding mechanism predictions for your favorite protein!
colab.research.google.com/github/eagal...

Also, we show that both the stability and cooperativity changes induced by mutations can be computed directly using sequence-based evolutionary models.
6/n

Protein topology imposes limits on the variability of folding cooperativity within a family. While most beta and alpha/beta structures exhibit only a few possible mechanisms despite high sequence diversity, alpha topologies allow for diverse folding scenarios.
5/n

For 15 diverse protein families, we computed the folding mechanisms of hundreds of proteins by simulating an Ising chain of folding elements, or foldons. The energetics is determined by each amino acid sequence.
4/n

We show that it is possible to use sequence info to go beyond predicting native structures and global stability to infer the folding mechanisms of globular proteins. We mapped a Potts evolutionary energy at the amino-acid level to a coarse-grained description of folding.
3/n

We know that closely related proteins usually share similar three-dimensional structures. But differences in their amino acid sequences can lead to distinct folding mechanisms, enabling the natural evolution of diverse biological functions.
2/n

Finally published!
“Inferring protein folding mechanisms from natural sequence diversity”

Open acces link: authors.elsevier.com/a/1lQvh1SPTB...
@biophysj.bsky.social

A new chapter of an amazing project w/ @diegulise.bsky.social and Ernesto Roman

1/n

Los detectives espaciales que desde Argentina buscan entender el Universo Se destacan en radioastronomía, astrobiología, física y geología planetaria. Quiénes son los científicos locales que buscan descifrar el Cosmos.

Investigadores que estudian el universo desde Argentina. Mi colaboración de hoy para Viva www.clarin.com/viva/detecti...

En ciencia no hay preguntas pequeñas, pero igualmente divierte investigar con @diegulise.bsky.social y Ezequiel Galpern por qué hay 20 aminoácidos en las proteínas y 4 nucleótidos en el ARN doi.org/10.1590/SciE...