Effects of Familial Alzheimer’s Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide

• Published in: The Journal of Physical Chemistry B
• Main Authors: Davidson, Darcy S., Kraus, Joshua A., Montgomery, Julia M., Lemkul, Justin A.
• Format: Text
• Language: English
• Published: 2022
• Subjects: Article; Arctic
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9547858/; http://www.ncbi.nlm.nih.gov/pubmed/36150020; https://doi.org/10.1021/acs.jpcb.2c03520

Familial Alzheimer’s disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer’s disease. FAD mutations such as “Iowa” (D23N), “Arctic” (E22G), “Italian” (E22K), and “Dutch” (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these mutations facilitate increased aggregation is unknown, but each mutation results in a change in net charge of the peptide. Previous studies have used nonpolarizable force fields to study Aβ, providing some insight into how this protein unfolds. However, nonpolarizable force fields have fixed charges that lack the ability to redistribute in response to changes in local electric fields. Here, we performed polarizable molecular dynamics (MD) simulations on the full-length Aβ(42) of WT and FAD mutations and calculated folding free energies of the Aβ(15–27) fragment via umbrella sampling. By studying both the full-length Aβ(42) and a fragment containing mutations and the central hydrophobic cluster (residues 17–21), we were able to systematically study how these FAD mutations impact secondary and tertiary structure and the thermodynamics of folding. Electrostatic interactions, including those between permanent and induced dipoles, affected sidechain properties, salt bridges, and solvent interactions. The FAD mutations resulted in shifts in the electronic structure and solvent accessibility at the central hydrophobic cluster and the hydrophobic C-terminal region. Using umbrella sampling, we found that the folding of the WT and E22 mutants are enthalpically driven, whereas the D23N mutant is entropically driven, arising from a different unfolding pathway and peptide-bond dipole response. Together, the unbiased, full-length and umbrella sampling simulations of fragments reveal that the FAD mutations perturb nearby residues and others in hydrophobic regions to potentially alter solubility. These results highlight the role electronic polarizability plays in amyloid misfolding and ...