Structural Quality, Not Quantity: Molecular Simulations of Protein Aggregation Dynamics.

Min-Yeh Tsai^1*

¹Chemistry and Biochemistry, National Chung Cheng University, Chiayi, Taiwan

* Presenter:Min-Yeh Tsai, email:myt@ccu.edu.tw

Protein aggregation represents a rich example of self-organization and phase-transition–like behavior in biological systems.
While conventional views emphasize the quantity of aggregation—such as oligomer size or growth rate—as the dominant control parameter, our recent coarse-grained molecular dynamics simulations reveal that it is the quality of structural organization that governs the emergent kinetics and functional outcomes. I will present three representative systems illustrating this principle.
1. Aβ42 peptides: monomer diffusion on twisted fibril surfaces shows how geometric frustration and surface roughness modulate nucleation kinetics.
2. TDP-43 proline variants: changes in local sequence stiffness drive transitions between ordered and disordered oligomer states, resembling order–disorder transitions in polymer systems.
3. Cofilin oligomers: interface-specific disulfide bonding controls higher-order assembly, highlighting how chemical connectivity constrains mesoscale organization.
Together, these studies point to a unifying principle: the structural order parameter—rather than aggregate number—determines the fate of protein assembly and regulation. This perspective links molecular biophysics with nonequilibrium statistical mechanics, suggesting new routes to describe and control protein aggregation as a complex emergent process.

Keywords: Protein Aggregation, Cytoskeleton, Molecular Dynamics Simulation