Abstract
Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-β 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-β (Aβ) 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 heterogenous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogenous amyloid oligomers of Aβ(16-22) and IAPP(20-29) 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, β-strand rich oligomers with Drude, structural rearrangement occurred causing some loss of β-strand structure in favor of random coil content for all oligomers. Homogenous Aβ(16-22) 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 Aβ(16-22) residues in heterogenous 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.