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

By Weikang Gong, Aysam Guerler, Chengxin Zhang, Elisa Warner, Chunhua Li, Yang Zhang

Posted 17 Oct 2020
bioRxiv DOI: 10.1101/2020.10.17.343962

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. ### Competing Interest Statement The authors have declared no competing interest.

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