Enhancement, dissemination and application of the PhyreRisk/Phyre resource for modelling protein structures and the effects of genetic variants (360G-Wellcome-218242_Z_19_Z)

We are applying to support the enhancement, dissemination and application of the PhyreRisk/Phyre resource. PhyreRisk ( http://phyrerisk.bc.ic.ac.uk ) caters for researchers studying human genetic variation. Through PhyreRisk, a user can map DNA variants, from either genomic or proteomic coordinates, onto experimental and Phyre-predicted protein structures. The Phyre web-server (www.sbg.bio.ic.ac.uk/phyre2 ) is a widely-used (>90,000 distinct users in 2018) ELIXIR-UK resource to predict protein structure from sequence. Additionally, our program Missense3D (http://www.sbg.bio.ic.ac.uk/~missense3d/ ) provides structure-based evidence for the effect of a missense variant. Funding will be used to develop the following new predictive features within Phyre for subsequent inclusion in PhyreRisk: (i) prediction of ligand/protein interactions, (ii) template-free tertiary structure prediction using contacts (iii) domain/domain packing. PhyreRisk will be markedly extended by: (i) increased structural coverage from Phyre and predicted complexes from our collaborator in Kansas (ii) enhancing Missense3D to include functional residues, protein/protein interactions and membrane-bound proteins to yield quantitative predictions (iii) the inclusion and subsequent analysis using Missense3D of genetic variants reported in major databases (e.g. gnomAD, ClinVar, COSMIC, Genomics England and UK-BioBank). (iv) linking PhyreRisk, particularly the structural data, to other resources including gnomAD. We will disseminate the resource via workshops, conference presentations and publications.