Reconstruction Puzzles

Started by agcohn821

agcohn821 Staff Lv 1

What are reconstruction puzzles? These are puzzles in which there's a known protein structure that's been solved by crystallography of cryo-EM before, but we have reason to believe that it could be improved. The factors we look at to decide whether this is the case are the statistics pertaining to quality of geometry and steric clashes as well as statistics on the fit of the protein to the electron density. Some of the reconstruction puzzles are older, when tools for solving structures were not as good, but some are newer. While the PDB has quality control metrics and flags structures for authors to work on, ultimately the system is designed to be permissive in what structures are deposited. As a result, Foldit Players can contribute by taking some of these structures that have issues and bringing them up to snuff.

Why is this important? There's a couple reasons, but it comes down to every structure in the PDB mattering. Sometimes, this has to do with our ability to use it as a database for things like machine learning, in which errors can cause problems. However, I like to think about it from the perspective that each structure tells us something that's unique in science. Science is meant to build off the discoveries of others, and this is the reason that the PDB is a public database; scientists download these structures to look for clues as to how the biology works, and they use those structures to design and interpret their own experiments. Mistakes in structures can then propagate to incorrect assumptions and conclusions down the road. Over time, these mistakes are found out, but potentially at the loss of a lot of time, money, and energy. It's better if we can nip it in the bud by improving the structures in the PDB themselves.

horowsah Staff Lv 1

Short answer- alphafold isn't really built for these particular problems, but looking at the best computational methods available, so far it seems like Foldit players definitely have something the computers don't as far as I an tell.

jeff101 Lv 1

If in one of these reconstruction puzzles we manage to improve a structure, how does the Foldit Staff then get our structure into the Protein Data Base? What have been some of our best successes to this end so far? Are any publications in the works about them? Just curious.

Thanks,
Jeff

rmoretti Staff Lv 1

The Protein Data Base proper typically doesn't take re-fitting from third parties. It's only if the group which was originally responsible for submitting the structure submits a correction that they will update the structure.

There are, however, other projects and databases which attempt to host the best-refitted structures, regardless of source. PDB-REDO (https://pdb-redo.eu/) is probably the best known of these. Hopefully it isn't "talking out of school" to mention that Foldit has been in contact with the people at PDB-REDO about submitting Foldit updated structures to their database. This is still a work-in-progress, so we don't have anything finalized on that yet. The pipeline is still in development, so it may be a bit before there are statistics/results/publications.

Artoria2e5 Lv 1

I've heard about PDB-REDO before and what they do is absolutely awesome. It would be very cool to have their metrics applied to player-reconstructed models to see how they score!