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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\u2019 theorem we estimate that a similarly small fraction (&lt;~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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010013","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T17:32:50Z","timestamp":1649698370000},"page":"e1010013","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Are transient protein-protein interactions more dispensable?"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8300-7360","authenticated-orcid":true,"given":"Mohamed Ali","family":"Ghadie","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5596-5518","authenticated-orcid":true,"given":"Yu","family":"Xia","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"issue":"4","key":"pcbi.1010013.ref001","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2016.01.029","article-title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing","volume":"164","author":"X Yang","year":"2016","journal-title":"Cell"},{"issue":"9","key":"pcbi.1010013.ref002","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg.2017.38","article-title":"Network propagation: a universal amplifier of genetic associations","volume":"18","author":"L Cowen","year":"2017","journal-title":"Nat Rev 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