| Summary: | Protein-protein interactions (PPIs) are key drivers of cell function and evolution. While it is widely assumed that most permanent PPIs are important for cellular function, it remains unclear whether transient PPIs are equally important. Here, we estimate and compare dispensable content among transient PPIs and permanent PPIs in human. Starting with a human reference interactome mapped by experiments, we construct a human structural interactome by building three-dimensional structural models for PPIs, and then distinguish transient PPIs from permanent PPIs using several structural and biophysical properties. We map common mutations from healthy individuals and disease-causing mutations onto the structural interactome, and perform structure-based calculations of the probabilities for common mutations (assumed to be neutral) and disease mutations (assumed to be mildly deleterious) to disrupt transient PPIs and permanent PPIs. Using Bayes' theorem we estimate that a similarly small fraction (<∼20%) of both transient and permanent PPIs are completely dispensable, i.e., effectively neutral upon disruption. Hence, transient and permanent interactions are subject to similarly strong selective constraints in the human interactome. © 2022 Ghadie, Xia. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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