Accurate model of liquid-liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties
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Accurate model of liquid-liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties. / Tesei, Giulio; Schulze, Thea K.; Crehuet, Ramon; Lindorff-Larsen, Kresten.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 44, e2111696118, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Accurate model of liquid-liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties
AU - Tesei, Giulio
AU - Schulze, Thea K.
AU - Crehuet, Ramon
AU - Lindorff-Larsen, Kresten
N1 - Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.
PY - 2021
Y1 - 2021
N2 - Many intrinsically disordered proteins (IDPs) may undergo liquid- liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residuelevel 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 residuespecificmodel parameters thatminimize 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 selfassociation and LLPS.
AB - Many intrinsically disordered proteins (IDPs) may undergo liquid- liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residuelevel 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 residuespecificmodel parameters thatminimize 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 selfassociation and LLPS.
KW - Biomolecular condensates
KW - Force field parameterization
KW - Intrinsically disordered proteins
KW - Liquid-liquid phase separation
KW - Protein interactions
U2 - 10.1073/pnas.2111696118
DO - 10.1073/pnas.2111696118
M3 - Journal article
C2 - 34716273
AN - SCOPUS:85119291695
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
M1 - e2111696118
ER -
ID: 286414371