Bhandari, K. | Search bioRxiv

bioRxiv2025

A Global Thermodynamic-Kinetic Model Capturing the Hallmarks of Liquid-Liquid Phase Separation and Amyloid Aggregation

Aberrant aggregation of proteins into amyloid fibrils is associated with numerous neurodegenerative, systemic and metabolic diseases. Amyloidogenic proteins undergo spontaneous liquid-liquid phase separation (LLPS), rapidly forming protein-rich condensates prior to fibrillization. However, the exact effects of LLPS on amyloid aggregation remain unclear as contrasting fibrillization-promotion, inhibition and even biphasic effects have been reported in the literature. In this study, we integrate LLPS-induced heterogeneity of protein concentrations into a thermodynamic-kinetic model of amyloid aggregation. We adopt the phase transition theory and introduce protein condensates as an additional protein state alongside non-interacting monomers, oligomers and fibrils. Oligomerization and fibrillization can occur both in the protein-rich condensates and the protein-poor solution. This model allows us to derive the time evolution of different states - monomers, condensates, oligomers, and fibrils - spanning a wide range of concentrations, and determine how model parameters related to LLPS, fibrillization, and oligomerization influence fibrillization kinetics. Using this global model, we resolve the seemingly contradictory effects of LLPS on fibrillization. We expect the developed thermodynamic-kinetic model of LLPS, and amyloid aggregation will help advance our understanding, modulation, and mitigation of pathological aggregation processes in amyloid diseases. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/655849v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@12eeb58org.highwire.dtl.DTLVardef@15cee66org.highwire.dtl.DTLVardef@278c10org.highwire.dtl.DTLVardef@5c8d4a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2020

Structure-function properties in disordered condensates

Biomolecular condensates appear throughout the cell serving a wide variety of functions. Many condensates appear to form by the assembly of multivalent molecules, which produce phase separated networks with liquid-like properties. These networks then recruit client molecules, with the total composition providing functionality. Here we use a model system of poly-SUMO and poly-SIM proteins to understand client-network interactions and find that the structure of the network plays a strong role in defining client recruitment, and thus functionality. The basic unit of assembly in this system is a zipper-like filament composed of alternating poly-SUMO and poly-SIM molecules. These filaments have defects of unsatisfied bonds that allow for both the formation of a 3D network and the recruitment of clients. The filamentous structure constrains the scaffold stoichiometries and the distribution of client recruitment sites that the network can accommodate. This results in a non-monotonic client binding response that can be tuned independently by the client valence and binding energy. These results show how the interactions within liquid states can be disordered yet still contain structural features that provide functionality to the condensate.

biophysics↗