Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Intrinsically disordered proteins (IDPs), like alpha-synuclein, adopt various conformations crucial for function and malfunction.
• Misfolding of alpha-synuclein is implicated in neurodegenerative diseases.
• IDP conformations are sensitive to pH due to their low hydropathy and high charge.

Purpose of the Study:

• To investigate the conformational ensembles of alpha-synuclein at neutral (pH 7) and acidic (pH 3) conditions.
• To compare computational findings with experimental data (smFRET, SAXS, NMR).
• To understand how pH-induced structural changes influence pathogenic fibril formation.

Main Methods:

• Employed a divide-and-conquer scheme for enhanced sampling of IDP structural ensembles.
• Constructed and analyzed conformational ensembles of alpha-synuclein at different pH values.
• Characterized conformational and dynamic differences between ensembles.

Main Results:

• Alpha-synuclein adopts a more compact state at low pH.
• Low pH causes C-terminal compaction due to residue neutralization, while overall end-to-end distance is maintained.
• Decreasing pH leads to increased hydrophilic interactions and altered intra-protein interactions.

Conclusions:

• pH-dependent conformational changes in alpha-synuclein are critical for its function and potential misfolding.
• Understanding these structural dynamics provides insights into preventing alpha-synuclein aggregation and associated pathologies.
• The study highlights the sensitivity of IDPs to environmental conditions like pH.