Missense3D-PPI: A Web Resource to Predict the Impact of Missense Variants at Protein Interfaces Using 3D Structural Data
Year: 2023
Type: article
Abstract: ABSTRACT In 2019, we released Missense3D which identifies stereochemical features that are disrupted by a missense variant, such as introducing a buried charge. Missense3D analyses the effect of a missense variant on a single structure and thus may fail to identify as damaging surface variants disrupting a protein interface i.e., a protein-protein interaction (PPI) site. Here we present Missense3D-PPI designed to predict missense variants at PPI interfaces. Our development dataset comprised of 1,279 missense variants (pathogenic n=733, benign n=546) in 434 proteins and 545 experimental structures of PPI complexes. Benchmarking of Missense3D-PPI was performed after dividing the dataset in training (320 benign and 320 pathogenic variants) and testing (226 benign and 413 pathogenic). Structural features affecting PPI, such as disruption of interchain bonds and introduction of unbalanced charged interface residues, were analysed to assess the impact of the variant at PPI. Missense3D-PPI’s performance was superior to that of Missense3D: sensitivity 42% versus 8% and accuracy 58% versus 40%, p=4.23×10 −16 However, the specificity of Missense3D-PPI was slightly lower compared to Missense3D (84% versus 98%). On our dataset, Missense3D-PPI’s accuracy was superior to BeAtMuSiC (p=2.3×10 −5 ), mCSM-PPI2 (p=3.2×10 −12 ) and MutaBind2 (p=0.003). Missense3D-PPI represents a valuable tool for predicting the structural effect of missense variants on biological protein networks and is available at the Missense3D web portal ( http://missense3d.bc.ic.ac.uk/missense3d/indexppi.html ).
Source: Journal of Molecular Biology
Institution: Imperial College London
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,970
Awards: FunPDBe - Community driven enrichment of PDB data with structural and functional annotations, Development and dissemination of a community tool for structure-based annotations of proteins in disease networks., 18-BBSRC-NSF/BIO - Structural modeling of interactome to assess phenotypic effects of genetic variation, Enhancement, dissemination and application of the PhyreRisk/Phyre resource for modelling protein structures and the effects of genetic variants, Enhancement, dissemination and application of the PhyreRisk/Phyre resource for modelling protein structures and the effects of genetic variants, Development and dissemination of a community tool for structure-based annotations of proteins in disease networks.
OpenAlex ID: W4360843077