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 -