Sequence dependent phase separation of protein-polynucleotide mixtures elucidated using molecular simulations
Year: 2020
Type: article
Abstract: Ribonucleoprotein (RNP) granules are membraneless organelles (MLOs), which majorly consist of RNA and RNA-binding proteins and are formed via liquid-liquid phase separation (LLPS). Experimental studies investigating the drivers of LLPS have shown that intrinsically disordered proteins (IDPs) and nucleic acids like RNA and other polynucleotides play a key role in modulating protein phase separation. There is currently a dearth of modelling techniques which allow one to delve deeper into how polynucleotides play the role of a modulator/promoter of LLPS in cells using computational methods. Here, we present a coarse-grained polynucleotide model developed to fill this gap, which together with our recently developed HPS model for protein LLPS, allows us to capture the factors driving protein-polynucleotide phase separation. We explore the capabilities of the modelling framework with the LAF-1 RGG system which has been well studied in experiments and also with the HPS model previously. Further taking advantage of the fact that the HPS model maintains sequence specificity we explore the role of charge patterning on controlling polynucleotide incorporation into condensates. With increased charge patterning we observe formation of structured or patterned condensates which suggests the possible roles of polynucleotides in not only shifting the phase boundaries but also introducing microscopic organization in MLOs.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkaa1099
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Funders: National Science Foundation, National Institutes of Health, Materials Research Science and Engineering Center, Harvard University, National Institute on Aging, Office of Naval Research, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Division of Materials Research, U.S. Naval Research Laboratory
Awards: G1051554911, G155958390, Materials Research Science and Engineering Center, G1859441762, Functional and Pathological Interactions of TDP-43, Liquid-Liquid Phase Separation in Heterochromatin Organization, G5651738850, Collaborative Research: Designing biomaterials through computational simulation and manipulation of phase behavior in a class of intrinsically disordered proteins, G7125181322, G761112474, G7701316025, Disentangling liquid-liquid phase separation and aggregation of intrinsically disordered proteins
OpenAlex ID: W3108187028