Abstract
Multivalent polymers are a key structural component of many biocondensates. When interacting with their cognate binding proteins, multivalent polymers such as RNA and modular proteins have been shown to influence the liquid-liquid phase separation (LLPS) boundary to both control condensate formation and to influence condensate dynamics after phase separation. Much is still unknown about the function and formation of these condensed droplets, but changes in their dynamics or phase separation are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s Disease. Therefore, investigation into how the structure of multivalent polymers relates to changes in biocondensate formation and maturation is essential to understanding and treating these diseases. Here, we use a coarse-grain, Brownian Dynamics simulation with reactive binding that mimics specific interactions in order to investigate the difference between non-specific and specific multivalent binding polymers. We show that non-specific binding interactions can lead to much larger changes in droplet formation at lower protein-polymer interaction energies than their specific, valence-limited counterparts. We also demonstrate the effects of solvent conditions and polymer length on phase separation, and we present how modulating binding energy to the polymer can change the organization of a droplet in a three component system of polymer, binding protein, and solvent. Finally, we compare the effects of surface tension and polymer binding on the condensed phase dynamics, and show that both lower protein solubilities and higher attraction/affinity of the protein to the polymer result in slower droplet dynamics. This research will help to better understand experimental systems and provides additional insight into how multivalent polymers can control LLPS.
Highlights
Multivalency is employed throughout biology for numerous reasons including building conformal interfaces, increasing specificity of bonds using a limited number of ligand types, and creating much stronger bonds by using many low affinity bonds simultaneously [1]
Multivalent species can come in many architectures, but here, we focus on multivalent polymers and their role in biocondensates or membraneless organelles
Our results suggest that even small changes in non-specific multivalent polymer-protein interactions can cause aberrant phase separation, whereas the systems are more robust to mutations in specific binding sites or valency
Summary
Multivalency is employed throughout biology for numerous reasons including building conformal interfaces, increasing specificity of bonds using a limited number of ligand types, and creating much stronger bonds by using many low affinity bonds simultaneously [1]. Multivalent binding is defined as when multiple binding sites on both interacting species bind. Multivalent polymers can control liquid-liquid phase separation. Fellowship and the Collamore-Rogers Fellowship through the Massachusetts Institute of Technology Office of Graduate Education. (https://oge.mit.edu/ finances/fellowships/odgefellowships) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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