PT  - JOURNAL ARTICLE
AU  - Tesei, Giulio
AU  - Schulze, Thea K.
AU  - Crehuet, Ramon
AU  - Lindorff-Larsen, Kresten
TI  - Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties
AID  - 10.1101/2021.06.23.449550
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.23.449550
4099  - http://biorxiv.org/content/early/2021/09/10/2021.06.23.449550.short
4100  - http://biorxiv.org/content/early/2021/09/10/2021.06.23.449550.full
AB  - Many intrinsically disordered proteins (IDPs) may undergo liquidliquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalisation of intracellular biochemical reactions. The phase behaviour of IDPs is sequence-dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intra- and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.Competing Interest StatementThe authors have declared no competing interest.