Folding the Protein Universe

March 3, 2021

Today signifies the realization of a long-held dream to have the structure of every (well nearly every) family in Pfam. The Pfam and InterPro databases have made available structural models of 6,370 protein families created by Ivan Anishchanka from David Baker’s group at the University of Washington in Seattle. The models are made using their latest prediction method called trRosetta which can predict protein structures, based on large multiple sequence alignments, with incredible accuracy.

The Baker group have had remarkable success over the years in the field of structure prediction, and in the recent CASP14 event the group’s predictions were the most accurate from an academic group. Although not quite as accurate as Deep Mind’s AlphaFold 2.0 predictions, they are certainly of a high enough quality for many applications. For example, I am interested to understand when a Pfam family is part of a larger superfamily, or clan as we call them in Pfam. I have been able to take the structural models and identify distant homologues in the PDB using tools such as DALI and PDBeFold that compare protein structures. For longer Pfam families we can look at the structure model and identify likely domain boundaries to split up the existing Pfam family into the domain sized chunks (for example Calmodulin_bind could be split into 3 domains).

Within the InterPro website we have developed a completely novel view that allows you to see which residues in the Pfam seed alignment are predicted to be close in space. By clicking on columns in the alignment, one can see where they are in the structural model and which residues are predicted to be nearby (see the documentation for further details). We would be very interested in getting your feedback on this feature. We could provide a similar view based on contacts found in known structures. The PDB file for individual models can be downloaded from the structural model tab on the family pages within the InterPro and Pfam websites. You can also download all of the structural model and contact map data from the Pfam ftp site and InterPro ftp site.

The figure above shows the contact map and structural model as seen through the InterPro website. Links to some example Pfam families that have a structure model are shown below (for the Pfam links, click on the Structural Model tab):

This is not the first time we have made a large set of structure predictions available.  Back in 2002, again in collaboration with David Baker and Rich Bonneau we made many models available.  The overall accuracy of these models was much lower and we did not know which models were good since we lacked an accurate quality metric. The new models come with a quality score called lDDT and broadly, we can consider a model with lDDT > 0.6 to be good, and one with lDDT > 0.8 to be excellent.

Today marks an amazing milestone, with 88% of Pfam families now having a PDB structure or a structural model. The story is not quite finished though, as there remain 2,202 families that do not have structural data. We plan to investigate different sequence sets to make an even larger set of models available in the coming months. We felt however that it was useful to release this data set to the community as fast as we could. The work described here has been possible only due to funding from the BBSRC BBR, which has been a critical part of the funding landscape for UK data resources for many years.

There will be many exciting stories to be told using this structural treasure trove, and we hope it is a beneficial resource to the community. Please let us know what you think of the data, and whether you find the contact maps and models useful.

Posted by Alex Bateman

One Response to “Folding the Protein Universe”


  1. […] on the tail of our inclusion of the Baker group’s trRosetta structural models we are excited to announce the inclusion of models from AlphaFold 2.0 generated by DeepMind and […]


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