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AmelieSchreiber 
posted an update Jan 3
Post
Currently attempting to hack EvoDiff to generate binders for target proteins with some interesting results. The generated binders tend to change conformation, sometimes drastically, when bound to the target proteins compared to their unbound states. Below is the target protein with an IDR linker, the generated binder, and the binder bound to the target protein with the IDR linker structure as predicted by ESMFold. Notice how the binder goes from being a solid alpha-helix, to being beta-sheets (in orange). That's quite a change in tertiary structure!
sbrandeis
•
edited Jan 4

Insightful, thank you for sharing!
Was the binder conformation change something you were expecting / looking for?

Link to EvoDiff preprint: https://www.biorxiv.org/content/10.1101/2023.09.11.556673v1

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AmelieSchreiber

It was unexpected. I believe finetuning may be in order and EvoDiff is not really intended to generate binders out-of-the-box anyway. Still though, the changes in tertiary structure for the generated protein are puzzling and interesting. How does an alpha-helix with an some higher pLDDT scores (middle picture of the unbound generated binder) turn into beta-sheets with low pLDDT scores in the presence of the target protein (picture on the right)? I find that strange and interesting. Is this a more extreme example of sampling multiple conformations of proteins that are fold-switching? (see https://www.biorxiv.org/content/10.1101/2023.12.16.571997v1)

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