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To understand the influences of crowding on chain compaction and phase separation (PS) behavior of disordered proteins, both experiments with synthetic crowders\u2014like polyethylene glycol (PEG) and ficoll\u2014and theoretical models and molecular simulation approaches have been applied. Here, we developed a residue\u2010based coarse\u2010grained model for PEG that is compatible with the protein CALVADOS model. To achieve this, we optimized model parameters by comparing simulations with experimental data on single\u2010chain PEG and on PEG\u2010induced compaction of disordered proteins. With our model we show how titrations of PEG can be used to quantify PS propensities of proteins that are not prone to phase separate strongly. We illustrate this for both variants of the low\u2010complexity domain of hnRNPA1 (A1\u2010LCD), and for wild\u2010type and a redesigned variant of \u03b1\u2010synuclein. Notably, we observe that the PEG crowding response changes between charge patterning variants of \u03b1\u2010synuclein, which is not the case for the variants that vary the number of aromatic residues in the A1\u2010LCD. We expect that our model will be useful for the interpretation of crowding experiments with disordered proteins, and we envisage it to be a starting point for explorations of proteins with weak propensities to phase separate.<\/jats:p>","DOI":"10.1002\/pro.70232","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T08:03:23Z","timestamp":1752739403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A coarse\u2010grained model for disordered proteins under crowded conditions"],"prefix":"10.1002","volume":"34","author":[{"given":"Arri\u00ebn Symon","family":"Rauh","sequence":"first","affiliation":[{"name":"Structural Biology and NMR Laboratory, Linderstr\u00f8m\u2010Lang Centre for Protein Science, Department of Biology University of Copenhagen  Copenhagen 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