Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.

Rationally and efficiently modifying the amino-acid sequence of proteins to control their ability to undergo liquid-liquid phase separation (LLPS) on demand is not only highly desirable, but can also help to elucidate which protein features are important for LLPS. Here, we propose a computational me...

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Autores principales:	Simon M Lichtinger, Adiran Garaizar, Rosana Collepardo-Guevara, Aleks Reinhardt
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8451791b5c80476b8177c2c6cc4e33b7
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spelling	oai:doaj.org-article:8451791b5c80476b8177c2c6cc4e33b72021-12-02T19:58:01ZTargeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.1553-734X1553-735810.1371/journal.pcbi.1009328https://doaj.org/article/8451791b5c80476b8177c2c6cc4e33b72021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009328https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Rationally and efficiently modifying the amino-acid sequence of proteins to control their ability to undergo liquid-liquid phase separation (LLPS) on demand is not only highly desirable, but can also help to elucidate which protein features are important for LLPS. Here, we propose a computational method that couples a genetic algorithm to a sequence-dependent coarse-grained protein model to evolve the amino-acid sequences of phase-separating intrinsically disordered protein regions (IDRs), and purposely enhance or inhibit their capacity to phase-separate. We validate the predicted critical solution temperatures of the mutated sequences with ABSINTH, a more accurate all-atom model. We apply the algorithm to the phase-separating IDRs of three naturally occurring proteins, namely FUS, hnRNPA1 and LAF1, as prototypes of regions that exist in cells and undergo homotypic LLPS driven by different types of intermolecular interaction, and we find that the evolution of amino-acid sequences towards enhanced LLPS is driven in these three cases, among other factors, by an increase in the average size of the amino acids. However, the direction of change in the molecular driving forces that enhance LLPS (such as hydrophobicity, aromaticity and charge) depends on the initial amino-acid sequence. Finally, we show that the evolution of amino-acid sequences to modulate LLPS is strongly coupled to the make-up of the medium (e.g. the presence or absence of RNA), which may have significant implications for our understanding of phase separation within the many-component mixtures of biological systems.Simon M LichtingerAdiran GaraizarRosana Collepardo-GuevaraAleks ReinhardtPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009328 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Simon M Lichtinger Adiran Garaizar Rosana Collepardo-Guevara Aleks Reinhardt Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
description	Rationally and efficiently modifying the amino-acid sequence of proteins to control their ability to undergo liquid-liquid phase separation (LLPS) on demand is not only highly desirable, but can also help to elucidate which protein features are important for LLPS. Here, we propose a computational method that couples a genetic algorithm to a sequence-dependent coarse-grained protein model to evolve the amino-acid sequences of phase-separating intrinsically disordered protein regions (IDRs), and purposely enhance or inhibit their capacity to phase-separate. We validate the predicted critical solution temperatures of the mutated sequences with ABSINTH, a more accurate all-atom model. We apply the algorithm to the phase-separating IDRs of three naturally occurring proteins, namely FUS, hnRNPA1 and LAF1, as prototypes of regions that exist in cells and undergo homotypic LLPS driven by different types of intermolecular interaction, and we find that the evolution of amino-acid sequences towards enhanced LLPS is driven in these three cases, among other factors, by an increase in the average size of the amino acids. However, the direction of change in the molecular driving forces that enhance LLPS (such as hydrophobicity, aromaticity and charge) depends on the initial amino-acid sequence. Finally, we show that the evolution of amino-acid sequences to modulate LLPS is strongly coupled to the make-up of the medium (e.g. the presence or absence of RNA), which may have significant implications for our understanding of phase separation within the many-component mixtures of biological systems.
format	article
author	Simon M Lichtinger Adiran Garaizar Rosana Collepardo-Guevara Aleks Reinhardt
author_facet	Simon M Lichtinger Adiran Garaizar Rosana Collepardo-Guevara Aleks Reinhardt
author_sort	Simon M Lichtinger
title	Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
title_short	Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
title_full	Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
title_fullStr	Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
title_full_unstemmed	Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
title_sort	targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8451791b5c80476b8177c2c6cc4e33b7
work_keys_str_mv	AT simonmlichtinger targetedmodulationofproteinliquidliquidphaseseparationbyevolutionofaminoacidsequence AT adirangaraizar targetedmodulationofproteinliquidliquidphaseseparationbyevolutionofaminoacidsequence AT rosanacollepardoguevara targetedmodulationofproteinliquidliquidphaseseparationbyevolutionofaminoacidsequence AT aleksreinhardt targetedmodulationofproteinliquidliquidphaseseparationbyevolutionofaminoacidsequence
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Targeted modulation of protein liquid-liquid phase separation by evolution of amino-acid sequence.

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