Guerler, A. | Search bioRxiv

bioRxiv2021

Fast and accurate genome-wide predictions and structural modeling of protein-protein interactions using Galaxy

Protein-protein interactions play a crucial role in almost all cellular processes. Identifying interacting proteins reveals insight into living organisms and yields novel drug targets for disease treatment. Here, we present a publicly available, automated pipeline to predict genome-wide protein-protein interactions and produce high-quality multimeric structural models. Application of our method to the Human and Yeast genomes yield protein-protein interaction networks similar in quality to common experimental methods. We identified and modeled Human proteins likely to interact with the papain-like protease of SARS-CoV2s non-structural protein 3 (Nsp3). We also produced models of SARS-CoV2s spike protein (S) interacting with myelin-oligodendrocyte glycoprotein receptor (MOG) and dipeptidyl peptidase-4 (DPP4). The presented method is capable of confidently identifying interactions while providing high-quality multimeric structural models for experimental validation. The interactome modeling pipeline is available at usegalaxy.org and usegalaxy.eu.

genomics↗

bioRxiv2020

Integrating multimeric threading with high-throughput experiments for structural interactome of Escherichia coli

Genome-wide protein-protein interaction (PPI) determination remains a significant unsolved problem in structural biology. The difficulty is twofold since high-throughput experiments (HTEs) have often a high false-positive rate in assigning PPIs, and PPI quaternary structures are more difficult to solve than tertiary structures using traditional structural biology techniques. We proposed a uniform pipeline to address both problems, which first recognizes PPIs by combining multi-chain threading alignments with HTE results using naive Bayesian classifiers, where the quaternary complex structures are then constructed by mapping the monomer models with the dimeric threading frameworks through interface-specific structural alignments. The pipeline was applied to the Escherichia coli genome and created 35,125 confident PPIs which is 4.5-fold higher than HTE alone. Graphic analyses of the PPI networks revealed a scale-free cluster size distribution, which was found critical to the robustness of genome evolution and the centrality of functionally important proteins that are essential to E. coli survival. Furthermore, complex structure models were constructed for all predicted E. coli PPIs based on the quaternary threading alignments, where 6,771 of them were found to have a high confidence score that corresponds to the correct fold of the complexes with a TM-score >0.5 and 93 showed a close consistency with the later released experimental structures with an average TM-score=0.73. These results demonstrated the significant usefulness of threading-based homologous modeling in both genome-wide PPI network detection and complex structural construction.

bioinformatics↗