Modulators Selectively Reshape alpha-Synuclein Phase Transitions

TL;DR

This study addresses how molecular modulators reshape alpha-synuclein phase transitions relevant to Parkinson's disease by using a coarse-grained Brownian-dynamics framework in which each alpha-synuclein monomer morphs between a disordered soft-sphere state and a beta-rich rod state, and modulators are fixed soft spheres. By varying modulator concentration and affinity toward disordered versus beta-rich states, the authors identify three distinct effects: non-specific modulators induce dynamic, liquid-like disordered heteroassemblies that extend the lag phase and sequester monomers; non-specific attractions to the disordered state shift the conformational ensemble toward oligomer formation and slower nucleation; beta-selective modulators accumulate on fibril surfaces and ends, causing shorter fibrils and occasional bundling via surface coating that blocks further growth. These results provide a quantitative design framework linking modulator properties to nucleation, elongation, and off-pathway trapping, with implications for therapeutic intervention strategies and tunable materials. The work offers mechanistic insight into how precise modulator properties can redirect protein phase transitions toward desired endpoints and may generalize to other polypeptides undergoing similar disordered-to-ordered transitions.

Abstract

Protein phase transitions govern numerous diseases, including neurodegenerative disorders such as Parkinson's and Alzheimer's. In Parkinson's disease, distinct species of the protein alpha-synuclein undergo phase transitions from highly disordered to ordered beta-rich states. The emerging species and transitions between them can be reshaped by chaperones, small molecules, peptides or antibodies. Here, we use coarse-grained simulations to understand the effect of modulators on the thermodynamics and kinetics of alpha-synuclein transformations and phase transitions. Each protein is represented as a single morphing particle that transforms from a soft sphere (disordered state) to a hard spherocylinder (beta-rich state), while modulators are modeled as soft isotropic particles mimicking small peptides. The results show that purely repulsive modulators do not alter the final outcome, i.e. fibrils form following the same mechanisms independently of the modulator concentration. Attractive interactions towards the disordered protein slow down fibril formation in a dose-dependent manner by stabilizing intermediate species, and strong attraction yields persistent disordered heteroclusters. In contrast, specific attraction to the beta-rich state results in shorter fibrils through direct modulator surface "capping" that introduce kinetic barriers to monomer templating at the fibril ends and inhibit lateral attachment. Together, these results link modulator properties and environmental conditions to the effects on nucleation, fibril elongation and off-pathway trapping, providing a quantitative roadmap for selecting modulator properties and strategies that redirect phase transitions toward desirable endpoints. Additionally, they provide guiding principles for the development of intervention strategies and the engineering of novel materials with tunable and responsive properties.

Figures (4)

• Figure 1: The internal potential plotted against the internal coordinate for $\varepsilon_\lambda^\text{S} = 3$ and $\varepsilon_\lambda^\text{R} = 2$, see Eq. (\ref{['Eq:LambdaPot']}). Shown are representative snapshots of $\alpha$-syn in the disordered state (purple sphere) and $\alpha$-syn in the $\beta$-rich ordered state (blue spherocylinder with red patches). The inset shows the modulator (light blue sphere). Note that only the protein particles are morphing between disordered and ordered states according to $\lambda$, while the modulator's state remains unchanged.
• Figure 2: Effects of repulsive modulators on $\alpha$-syn clustering. (a) Number of clusters as a function of time at different modulator concentrations. (b) Time series of the average protein conformation in the simulation box at different modulator concentrations.
• Figure 3: Effects of modulator concentration and non-specific binding to the disordered protein. (a) Number of emerging clusters as a function of modulator concentration. (b) Violin plot of the protein conformations at high affinity of the modulators towards the disordered proteins. (c) Snapshots highlighting two-step nucleation at moderate modulator-protein attraction, $\mathcal{C}_{MS}^$=5 and $\mathrm{c_M}$=32.5 $\mu$M. (d) Representative snapshots of the emerging structures at $\mathrm{c_M}$=0 $\mu$M, $\mathrm{c_M}$=13 $\mu$M and $\mathrm{c_M}$=32.5 $\mu$M.
• Figure 4: Effects of $\beta$-specific modulators on $\alpha$-syn fibrillization. (a) Number of protein clusters as a function of modulator concentration. (b) Time series of the number of $\beta$-rich proteins at different modulator concentrations and high modulator-$\beta$-rich protein affinity, $\mathcal{C}_{MR}^$=10. (c-d) Time series of the type and size of the emerging clusters at $\mathrm{c_M}$=5$\mu$M and $\mathrm{c_M}$=32.5$\mu$M, respectively. The symbol color encodes cluster type, i.e., red for disordered, blue for $\beta$-rich and yellow for intermediate internal states, and symbol area encodes the cluster size. (e) Representative snapshot of an $\alpha$-synuclein fibril at $\mathrm{c_M}$=5$\mu$M and (f) at $\mathrm{c_M}$=32.5$\mu$M. At high modulator concentration the emerging fibrils are shorter due to the accumulation of modulators on the fibril surface thereby blocking incoming monomers to attach and continue fibrillar growth.