Systematic Characterization of Wild Type and Familial Alzheimer's Disease Mutant Aβ Monomers Through the Convergence of Ensembles Simulated with Different Force Fields

Amyloid β (Aβ) monomers represent the base state in the pathways of aggregation that result in the fibrils and oligomers involved in Alzheimer's disease (AD). The structural properties of these intrinsically disordered peptides remain unclear despite extensive efforts to resolve these through experiment and computation. Comparison of all-atom, explicitly solvated simulations of wild type Aβ monomers simulated with different force fields (OPLS-AA/L and AMBER99sb-ILDN) and water models (TIP3P and TIP4P-Ew) nevertheless demonstrate a convergence in structural properties and good agreement with experimental NMR observables. In Aβ42, antiparallel β-hairpin structure between L17-A21, A30-L34, and V40-I41 is prevalent in these ensembles. While residues 21-30 forms an interceding region in both simulations that rarely interacts with the majority of the protein, the structure of this region and the electrostatic interactions that characterize it are notably different between the two. To further explore these differences, NMR experiments and simulations using both combinations have been conducted for familial AD (FAD) mutations that perturb residues 22 and 23, observed in our wild type Aβ simulation data to be pivotal in determining the structure of this central region. The characterizations made here suggest simulation conditions that best reproduce the experimental data and help clarify how FAD mutations drive Aβ to aberrant aggregation pathways that result in disease phenotypes.