Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit...

Area of Science:

• Biochemistry
• Neuroscience
• Computational Biology

Background:

• Protein misfolding and aggregation are central to neurodegenerative diseases such as Alzheimer's and Parkinson's.
• Investigating early aggregation stages, particularly soluble oligomers, is crucial but experimentally challenging.
• Experimental evidence suggests amyloid-beta 42 (Aβ42) and alpha-synuclein (α-Syn) can coassemble.

Purpose of the Study:

• To investigate the interaction between Aβ42 and α-Syn monomers.
• To explore the formation of stable heterodimeric complexes between Aβ42 and α-Syn.
• To provide an atom-level model of early aggregation mechanisms in neurodegenerative diseases.

Main Methods:

• Utilized Amber and CHARMM force fields with implicit and explicit solvent models.
• Employed replica exchange and conventional simulation modes for comprehensive analysis.
• Assessed force field and solvent model performance against experimental and theoretical data.

Main Results:

• Aβ42 and α-Syn monomers form stable heterodimers with stronger interactions than Aβ42 dimers.
• α-Syn binding to Aβ42 reduces Aβ42's fibril-prone conformations and alters its properties.
• Explicit solvent simulations with specific force fields showed Aβ42 increases α-Syn's β-content, consistent with experimental aggregation triggers.

Conclusions:

• The study confirms the formation of stable Aβ42-α-Syn heterodimers.
• Explicit solvent simulations are more reliable for preserving structural properties of these proteins and their complexes.
• Findings offer insights into early aggregation stages of Alzheimer's and Parkinson's diseases at the atomic level.