Protein compactness and interaction valency define the architecture of a biomolecular condensate across scales

Anton A. Polyansky (Corresponding author), Laura D. Gallego, Roman G. Efremov, Alwin Köhler, Bojan Zagrovic

Publications: Contribution to journalArticlePeer Reviewed

Abstract

Non-membrane-bound biomolecular condensates have been proposed to represent an important mode of subcellular organization in diverse biological settings. However, the fundamental principles governing the spatial organization and dynamics of condensates at the atomistic level remain unclear. The Saccharomyces cerevisiae Lge1 protein is required for histone H2B ubiquitination and its N-terminal intrinsically disordered fragment (Lge11-80) undergoes robust phase separation. This study connects single-and multi-chain all-atom molecular dynamics simulations of Lge11-80 with the in vitro behavior of Lge11-80 condensates. Analysis of modeled protein-protein interactions elucidates the key determinants of Lge11-80 condensate formation and links configurational entropy, valency, and compactness of proteins inside the condensates. A newly derived analytical formalism, related to colloid fractal cluster formation, describes condensate architecture across length scales as a function of protein valency and compactness. In particular, the formalism provides an atomisti-cally resolved model of Lge11-80 condensates on the scale of hundreds of nanometers starting from individual protein conformers captured in simulations. The simulation-derived fractal dimensions of condensates of Lge11-80 and its mutants agree with their in vitro morphologies. The presented framework enables a multiscale description of biomolecular condensates and embeds their study in a wider context of colloid self-organization.

Original languageEnglish
Article numbere80038
JournaleLife
Volume12
DOIs
Publication statusPublished - 20 Jul 2023

Austrian Fields of Science 2012

  • 106023 Molecular biology

Keywords

  • Large1
  • S. cerevisiae
  • biomolecular condensate
  • colloid
  • disordered protein
  • fractal cluster
  • liquid-liquid phase separation
  • molecular biophysics
  • physics of living systems
  • structural biology

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