Experimental assessment of AI-based interactome mapping
Abstract
Abstract Genotype-phenotype relationships are mediated through intricate networks of physical and functional interactions among macromolecules. Knowledge of the interactome is vital to understand and model genetics and cellular biology. Recent advances in accurately predicting tertiary protein structures using artificial intelligence (AI) approaches such as AlphaFold 1 have revived the vision that the protein-protein interactome might be fully predictable through computational modeling of quaternary structures. Here we present a comprehensive experimental framework to systematically assess the impact of AI-driven interactome predictions for yeast 2 and human 3 . We find that the quality of high-confidence predictions is on par with established experimental approaches. However, in proteome-wide screening, the tested AI approaches underperform in the discovery of strictly novel protein-protein interactions (PPIs) compared to experimental reference interactome maps. In particular, the yeast interactome map described here identifies >40-fold more novel PPIs than its AI counterpart. Strikingly, AlphaFold provides structural models for a substantial number of experimentally identified PPIs missed by the virtual screens. Our results suggest that, at this stage, the main contribution of AI predictions is to provide quaternary structure models for experimentally identified PPIs.
Article Details
Authors (45)
Luke Lambourne
Anupama Yadav
Yang Wang
Alice Desbuleux
Dae-Kyum Kim
Florent Laval
Kerstin Spirohn-Fitzgerald
Tiziana Cafarelli
Carles Pons
István A. Kovács
Noor Jailkhani
Sadie Schlabach
David De Ridder
Katja Luck
Vladimir V. Botchkarev
Olivia Debnath
Wenting Bian
Yun Shen
Zhipeng Yang
Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University
Miles W. Mee
Mohamed Helmy
Yves Jacob
Unité de Génétique Moléculaire des Virus à ARN, CNRS UMR 3569, Département Virologie, Institut Pasteur
Irma Lemmens
Thomas Rolland
Gregory G. McClain
Atina G. Coté
Marinella Gebbia
Nishka Kishore
Jennifer J. Knapp
Joseph C. Mellor
Gonen Memisoglu
Jüri Reimand
Jan Tavernier
Michael E. Cusick
Quan Zhong
Patrick Aloy
Tong Hao
Benoit Charloteaux
Frederick P. Roth
Javier De Las Rivas
Pascal Falter-Braun
David E. Hill
Michael A. Calderwood
Jean-Claude Twizere
Marc Vidal