Non-Fickian diffusion within assemblies of the intrinsically disordered protein β-casein

Area of Science:

• Biophysics
• Structural Biology
• Protein Dynamics

Background:

• Understanding molecular mechanisms in intrinsically disordered protein (IDP) assemblies is vital for cellular stability and disease.
• Internal fluctuations govern the dynamics of regulated and toxic protein aggregates.
• Current knowledge of these dynamics, especially anomalous diffusion, remains limited.

Purpose of the Study:

• To investigate the molecular mechanisms of internal fluctuations in IDP assemblies.
• To probe the motions of alpha-casein, a model IDP, within its assemblies.
• To elucidate the origins of anomalous diffusion in such systems.

Main Methods:

• Utilized high-resolution quasi-elastic neutron scattering (QENS).
• Combined QENS with all-atom molecular dynamics (MD) simulations.
• Analyzed the motions of alpha-casein within its assemblies.

Main Results:

• Discovered a slow relaxation process exhibiting anomalous non-Fickian diffusion.
• Identified a continuous mobility gradient within the assembly, from dense core to exterior.
• Demonstrated that dynamic heterogeneity and crowding cause deviations from Fickian diffusion.

Conclusions:

• Anomalous diffusion in IDP assemblies arises from dynamic heterogeneity and density gradients.
• This behavior differs significantly from well-folded protein clusters.
• The findings extend the applicability of diffusion models to complex biological systems.