Conformational Ensemble Dynamics of Intrinsically Disordered Full-Length α- and β-Synuclein Monomers.

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Abnormal alpha-synuclein (αS) aggregation into amyloid fibrils is a hallmark of Parkinson's disease.
• Beta-synuclein (βS), a homologue, resists amyloid formation and can inhibit αS aggregation, but its structural dynamics are poorly understood.

Purpose of the Study:

• To investigate how sequence variations between αS and βS influence their structural dynamics and conformational landscapes.
• To elucidate the molecular mechanisms underlying their distinct aggregation propensities.

Main Methods:

• 100 independent 1000 ns atomistic discrete molecular dynamics simulations of αS and βS monomers.
• Free-energy landscape analysis to understand thermodynamic contributions (enthalpy-entropy trade-off).

Main Results:

• Both αS and βS are predominantly intrinsically disordered, with transient helices and β-sheets.
• The aggregation-prone nonamyloid component (NAC) region of αS favors dynamic β-sheets, while βS favors dynamic helices.
• Thermodynamic analysis shows structured states are enthalpy-driven, disordered states are entropy-driven, with αS favoring β-sheets and βS favoring helices.

Conclusions:

• Sequence differences dictate distinct conformational preferences and thermodynamic landscapes for αS and βS.
• These insights provide a mechanistic basis for αS aggregation in disease and βS's protective role.
• The study establishes a thermodynamic framework for understanding synuclein protein function and dysfunction.