Journey through Amyloid Protein Structures: Mapping Conformational Changes from Disorder to Aggregation with MD Simulations

Moritz Schäffler, Mohammed Khaled, Birgit Strodel

Amyloid-β peptide (Aβ) plays a critical role in Alzheimer's disease, particularly in its neurotoxic, smaller oligomeric forms. Experimental challenges complicate the study of these transient structures, which has led us to utilize advanced molecular dynamics (MD) simulations and analysis techniques that include methods to calculate free energies and mean first passage time distributions to identify metastable states and frustrations in the energy landscape. This combination of methods applied to Aβ reveals the structural intricacies of the peptide and reveals its transformative journey from disorder to order through interactions with other biomolecules, including other Aβ peptides. In particular, a stable β-hairpin motif emerges during self-assembly that favors ordered oligomers with a higher propensity to aggregate. Exploring the conformational landscape of Aβ improves our understanding of its dynamics and provides insights that are critical for therapeutic interventions in Alzheimer's disease.