Conformational Plasticity in α-Synuclein and How Crowded Environment Modulates It

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• Alpha-synuclein (αS) is a 140-residue intrinsically disordered protein (IDP).
• Its conformational plasticity is sensitive to environmental factors.
• Distinguishing aggregation-prone from aggregation-resistant states in αS remains challenging.

Purpose of the Study:

• To identify distinct metastable conformational states of αS in aqueous media.
• To investigate how crowded environments modulate these states and their equilibrium.
• To understand the impact of crowding on αS dimerization and aggregation propensity.

Main Methods:

• Utilized a 73 μs molecular dynamics ensemble.
• Constructed a comprehensive Markov state model (MSM).
• Simulated αS in both aqueous and crowded environments.

Main Results:

• Identified distinct metastable states for αS, with the most populated state aligning with PRE-NMR data.
• Observed non-monotonic compaction of αS conformations in crowded environments.
• Found that crowding accelerates αS dimerization and can promote or inhibit aggregation.

Conclusions:

• Crowded environments significantly modulate the conformational landscape of intrinsically disordered proteins like αS.
• These modulations can influence the balance between functionally relevant and aggregation-prone states.
• Understanding these effects is crucial for comprehending protein behavior in cellular environments.