Sticky Situations: A Mechanism for Biomolecular Condensate Aging Using Coarse-Grained Molecular Dynamics Simulations

Abstract

Biomolecular condensates, membraneless compartments found ubiquitously within eukaryotic cells, regulate cellular organization and biochemistry. Forming via liquid-liquid phase separation (LLPS), these complexes typically behave like droplets, fusing and flowing the way a liquid might. However, issues within the cell, including neurodegenerative diseases like ALS, induce a liquid-to-solid transition within condensates known as aging. Aging is detrimental to condensates as they rely on their liquid properties to adequately function, yet the molecular mechanism that drives these droplets to enter a solid-like, arrested state remains poorly understood. We seek to propose a valid mechanism for condensate aging that is both generalizable and agrees with observed biological behavior. Using coarse-grained molecular dynamics simulations through the program LAMMPS, we show that condensates become dynamically arrested through the formation of laddered constructs within the system that effectively freeze polymer movement. Building on a theoretical framework of conformational entropy, we find that aging is the result of molecular-level choices and dynamics. Crosslinkers between polymers converge to adjacent binding sites in order to minimize the entropic cost of forming bonds. Following the formation of these bonds, we see that more rigid polymers experience fewer fluctuations and can extend the lifetime of these linker ladders. The accumulation of linkers and maintenance of ladders through the simulation ultimately leads to the slowing of dynamics and structural hardening associated with the macroscopic event of condensate aging. By illuminating how simple physical mechanisms motivate complex cell-level outcomes, we hope to lay the groundwork for future research in biomolecular condensates and neurodegenerative diseases.