Topsy-Turvy: integrating a global view into sequence-based PPI prediction

By Rohit Singh, Kapil Devkota, Samuel Sledzieski, Bonnie Berger, Lenore J. Cowen. 2022

48 citations recorded by the source corpus.

Abstract Summary Computational methods to predict protein–protein interaction (PPI) typically segregate into sequence-based ‘bottom-up’ methods that infer properties from the characteristics of the individual protein sequences, or global ‘top-down’ methods that infer properties from the pattern of already known PPIs in the species of interest. However, a way to incorporate top-down insights into sequence-based bottom-up PPI prediction methods has been elusive. We thus introduce Topsy-Turvy, a method that newly synthesizes both views in a sequence-based, multi-scale, deep-learning model for PPI prediction. While Topsy-Turvy makes predictions using only sequence data, during the training phase it takes a transfer-learning approach by incorporating patterns from both global and molecular-level views of protein interaction. In a cross-species context, we show it achieves state-of-the-art performance, offering the ability to perform genome-scale, interpretable PPI prediction for non-model organisms with no existing experimental PPI data. In species with available experimental PPI data, we further present a Topsy-Turvy hybrid (TT-Hybrid) model which integrates Topsy-Turvy with a purely network-based model for link prediction that provides information about species-specific network rewiring. TT-Hybrid makes accurate predictions for both well- and sparsely-characterized proteins, outperforming both its constituent components as well as other state-of-the-art PPI prediction methods. Furthermore, running Topsy-Turvy and TT-Hybrid screens is feasible for whole genomes, and thus these methods scale to settings where other methods (e.g. AlphaFold-Multimer) might be infeasible. The generalizability, accuracy and genome-level scalability of Topsy-Turvy and TT-Hybrid unlocks a more comprehensive map of protein interaction and organization in both model and non-model organisms. Availability and implementation https://topsyturvy.csail.mit.edu. Supplementary information Supplementary data are available at Bioinformatics online.

Subfields: Genetics, Molecular Biology

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In Genetics

  1. Jian Peng
  2. Bonnie Berger

In Molecular Biology

  1. Jianzhu Ma
  2. Jian Peng
  3. Jinbo Xu
  4. Bonnie Berger
  5. Shitong Luo
  6. Sheng Wang
  7. Shiwang Liu
  8. Siqi Sun

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