Transmembrane β-Barrel Models of α-Synuclein Oligomers

Area of Science:

• Structural biology
• Neuroscience
• Biophysics

Background:

• Alpha-synuclein aggregation is linked to Parkinson's disease and Multiple System Atrophy.
• The cytotoxic mechanisms of alpha-synuclein oligomers, particularly their interaction with cell membranes, remain unclear.
• High-resolution structures of membrane-embedded alpha-synuclein oligomers are currently unavailable.

Purpose of the Study:

• To construct and evaluate potential transmembrane β-barrel structures formed by alpha-synuclein.
• To investigate the stability and structural dynamics of these putative membrane-embedded complexes.
• To explore the role of specific protein regions (NAC, 35-56) and histidine protonation in barrel formation and stability.

Main Methods:

• Sequence analysis to identify potential membrane-embedded β-hairpin regions within alpha-synuclein.
• Computational modeling of β-barrels formed by the NAC (64-92) and 35-56 regions.
• Molecular dynamics simulations (implicit membrane pores and all-atom simulations up to 10 μs) to assess barrel stability and hydration.

Main Results:

• A β-barrel formed by the NAC region (64-92) demonstrated stable insertion and hydration within the membrane for over 10 μs.
• A β-barrel formed by the 35-56 region showed stable insertion but dehydrated and collapsed under neutral His50 conditions or His50-to-Q mutation.
• Protonation of His50 residues in the 35-56 barrel resulted in an oval shape and maintained hydration for at least 10 μs.

Conclusions:

• Transmembrane β-barrels formed by alpha-synuclein, particularly the NAC region, can be stable membrane-embedded structures.
• The stability and hydration of the 35-56 region barrel are sensitive to histidine protonation, suggesting a role in disease pathology.
• These findings provide structural insights into potential mechanisms of alpha-synuclein-induced cytotoxicity in neurodegenerative diseases.