Initial Structural Models of the Aβ42 Dimer from Replica Exchange Molecular Dynamics Simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Amyloid (A)β oligomers are implicated in Alzheimer's disease pathogenesis.
• Experimental structural characterization of toxic Aβ oligomers is challenging due to their transient nature.

Purpose of the Study:

• To explore the link between Aβ monomer structure and the intermonomer interface properties in Aβ42 dimers.
• To understand how monomer structural features influence dimer formation and potential aggregation pathways.

Main Methods:

• Microsecond timescale implicit solvent replica exchange molecular dynamics simulations to sample monomer conformations.
• Protein-protein docking to build structural models of Aβ42 dimers.
• Analysis of monomer structures and their impact on dimer interface formation.

Main Results:

• Formation of an intramonomer salt bridge (Asp23-Lys28) hinders the development of a hydrophobic interface between central hydrophobic clusters (CHCs) in Aβ42 dimers.
• The salt bridge affects hydrophobic residue packing, reducing contacts between the CHC domain and C-terminal residues in monomers.
• This structural feature influences the propensity for hydrophobic interactions crucial for dimerization.

Conclusions:

• The Asp23-Lys28 salt bridge in Aβ42 monomers plays a critical role in modulating dimer interface formation.
• Findings suggest a mechanism by which monomer structure dictates aggregation pathways, potentially differentiating neurotoxic oligomers from inert fibrils.
• This structural insight could inform the development of diagnostics and therapies for Alzheimer's disease.