BBSRC-NSF/BIO - Expanding fold library in the twilight zone to facilitate structure determination of macromolecular machines

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The Protein Data Bank (PDB) is the single global archive of three-dimensional (3D) structures of large biological molecules. PDBe (pdbe.org) is the European partner in the global consortium managing the PDB. PDB is one of the oldest biological archives, with 144,000+ entries and nearly 2 million downloads daily by users worldwide in academic or industry settings, working on topics ranging from food security, human health through to design of more efficient enzymes in various aspects of biotechnology. Despite a steady increase in its holdings (13,000+ entries added in 2017), the growth of the PDB is far outstripped by the growth in the available protein sequence data. Resources like Genome3D (genome3d.eu), funded by the BBSRC, aim to fill the gap in structure coverage of the protein sequence space with reliable predictions of structures. This resource combines data from a number of UK and overseas groups who apply complementary methods for protein structure prediction. These approaches largely model proteins that are closely related to a protein of known structure (ie the protein relatives share more than 30% identical residues in their sequences). The Rosetta method for predicting protein structures, a world-leading approach developed by the Baker lab in the USA, was recently enhanced with information derived from evolutionary analyses of protein sequence data, yielding reliable models even for cases where sequence identity between the model and the available experimental structures is very low (below 30%). We will integrate Rosetta models into Genome3D to expand the coverage of structural data for important organisms for health (e.g. human) and food security (e.g. wheat).This project will also enrich both the experimentally determined and computationally predicted structures with valuable functional annotations, such as information pertaining to surface interfaces, a key ingredient in understanding how proteins interact with each other and with other biological molecules. By focussing on proteins dissimilar to those with known structures, this portal will help fill the gaps in structure coverage of the protein sequence space and will make structure data much more readily available and accessible. Finally, novel visualisation tools integrating the presentation of the predicted and experimentally determined structures will be developed, maintaining a clear distinction between what is predicted and what is experimentally determined. The expanded set of 3D models derived from this project will in turn help to expand the coverage of sequence space even further, since these models can be used to guide the experimental determination of protein structures being obtained by powerful new structural biology techniques like cryo-Electron Microscopy (EM). This project will also endeavour, where possible, to improve the assembly of individual protein structures into macromolecular complexes which can be analysed to determine their biological role. We anticipate that scientists in both academia and industrial sectors (e.g. pharmaceutical companies) will benefit from access to such an integrated portal, assisting them in designing new medicines, understanding the mechanism of disease, or in designing proteins with novel properties. Recent "resolution revolution" in Electron Microscopy allows near routine determination of structures of large molecular machines, and is in need of a large repertoire of "building blocks" in interpreting the experimental results, a need which will be partially addressed by the new portal and its provision of expanded domain structure libraries. The portal will also have ways to access the assembled data programmatically, benefiting power users: software developers and maintainers of other resources.