Global Analysis of Aggregation Determinants in Small Protein Domains www.biorxiv.org/content/10.1101/2025.11....

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Small proteins can be more complex than they look!

We know proteins fluctuate between different conformations- but by how much? How does it vary from protein to protein? Can highly stable domains have low stability segments? @ajrferrari.bsky.social experimentally tested >5,000 domains to find out!

Large-scale discovery, analysis, and design of protein energy landscapes www.biorxiv.org/content/10.1101/2025.03....

A tremendous thank you to Gabe and members of the Rocklin lab for their feedback! 8/8

And we explore how Ala and Gly insertions at the same position can have very different effects! 7/8

The Pin1 WW domain example illustrates how deletions can stabilize a domain by relieving backbone strain 6/8

Using the Rosetta energy function, we see that stabilizing deletions (but not insertions) are often found in regions of higher backbone strain 5/8

Additionally, we find that Rosetta’s energy function outperforms an ESM-IF based analysis in predicting mutational effects of stabilizing indels 4/8

Using ColabFold predicted structures of stabilized variants, we show that most indel mutations cause minimal structural perturbations 3/8

We analyzed 103 stabilizing amino acid indel mutants of 48 diverse natural and designed small protein domains 2/8

Structural and energetic analysis of stabilizing indel mutations Amino acid insertions and deletions (indels) are among the most common protein mutations and necessitate changes to a protein’s backbone geometry. Examining how indels affect protein folding stability...

I'm super excited to share my recent work with @grocklin.bsky.social “Structural and energetic analysis of stabilizing indel mutations” biorxiv.org/content/10.1.... 1/8