Biological condensates form percolated networks with molecular motion properties distinctly different from dilute solutions

Abstract

Formation of membraneless organelles or biological condensates via phase separation hugely expands cellular organelle repertoire. Biological condensates are dense and viscoelastic soft matters instead of canonical dilute solutions. Unlike discoveries of numerous different biological condensates to date, mechanistic understanding of biological condensates remains scarce. In this study, we developed an adaptive single molecule imaging method that allows simultaneous tracking of individual molecules and their motion trajectories in both condensed and dilute phases of various biological condensates. The method enables quantitative measurements of phase boundary, motion behavior and speed of molecules in both condensed and dilute phases as well as the scale and speed of molecular exchanges between the two phases. Surprisingly, molecules in the condensed phase do not undergo uniform Brownian motion, but instead constantly switch between a confined state and a random motion state. The confinement is consistent with formation of large molecular networks (i.e., percolation) specifically in the condensed phase. Thus, molecules in biological condensates behave distinctly different from those in dilute solutions. This finding is of fundamental importance for understanding molecular mechanisms and cellular functions of biological condensates in general.