No abstract

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 the 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 simulations on the full-length Aβ42 of WT and FAD mutations and calculated folding free energies of the Aβ15–27 fragment via umbrella sampling. By studying both the full-length Aβ42 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 side-chain 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 is 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 the role of heterogeneous microenvironments that arise as conformational change takes place.

Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-[Formula: see text] oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-[Formula: see text] (A[Formula: see text] and islet amyloid polypeptide (IAPP), which are involved in the pathology of Alzheimer’s disease and Type 2 diabetes mellitus, respectively. In addition to forming homogenous oligomers and fibrils, these species have been found to cross-aggregate in heterogeneous structures. Biophysical properties, including electronic effects, that are unique or conserved between homogenous and heterogeneous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogeneous amyloid oligomers of A[Formula: see text] and IAPP[Formula: see text] fragments using the Drude oscillator model to investigate the impact of electronic polarization on the structural morphology and stability of preformed hexamers. Upon simulation of preformed, [Formula: see text]-strand rich oligomers with Drude, structural rearrangement occurred causing some loss of [Formula: see text]-strand structure in favor of random coil content for all oligomers. Homogenous A[Formula: see text] was the most stable system, deriving stability from low polarization in hydrophobic residues and through salt bridge formation. Changes in polarization were observed primarily for A[Formula: see text] residues in heterogeneous cross-amyloid systems, displaying a decrease in charged residue dipole moments and an increase in hydrophobic sidechain dipole moments. This work is the first study utilizing the Drude-2019 force field with amyloid oligomers, providing insight into the impact of electronic effects on oligomer structure and highlighting the importance of different microenvironments on amyloid oligomer stability.

No abstract

Many diseases are associated with aberrant protein aggregation. Recently, there has been resurgent interest in co-opting the framework of phase transitions to understand the distinct concentration thresholds separating different phases of aggregation-prone molecules. This analogy, which was purely conceptual, has now been shown to have quantitative significance. Importantly, instead of searching for elusive ''toxic conformations'', dealing