The unfolding and aggregation of the amyloid β-peptide (Aβ) is an underlying component of the pathology of Alzheimer’s disease. The exact molecular details of the aggregation pathway are still unknown, as is the mechanism by which the peptides convert from a membrane-bound, partially α-helical form, to a disordered ensemble in solution. The vast majority of Alzheimer’s cases arise from wild-type Aβ, but a small number originate from familial mutations. These mutations are typically single substitutions within the Aβ sequence, allowing for a systematic comparison of (1) unfolding pathways and (2) conformational ensembles in solution. Here, we applied polarizable molecular dynamics simulations using the Drude-2019 force field to study the full-length (42-residue) form of wild-type Aβ and four key mutants (E22G, E22K, E22Q, and D23N). Our simulations revealed differences in secondary and tertiary structure among these variants, and alterations to tertiary contacts give rise to unique microenvironments that subtly alter dipole moments of residues in the Aβ sequence. These perturbations could have implications for the resulting ability of the peptides to aggregate. We augmented the full-length simulations with umbrella sampling simulations of the fragment of Aβ encompassing residues 15-27 to quantify the free energy of unfolding as a function of mutation, which was further assessed as a function of temperature to delineate the contributions of enthalpy and entropy to the unfolding free energy. The use of a polarizable force field also enabled us to determine the role of backbone hydrogen bonding cooperativity to the unfolding process, which is similar for the WT and E22 mutants but proceeds differently for the D23N mutant.

Dipole-dipole interactions modulate secondary and tertiary structure of wild-type and mutant amyloid β-peptides

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.