Alzheimer’s disease (AD) is a fatal neurodegenerative disorder characterized by an abnormal accumulation of the amyloid-β (Aβ) and its subsequent aggregation into oligomers, fibrils, and plaques. This accumulation has been linked to the disruption of neuronal networks, resulting in cerebral atrophy and cognitive decline. AD is one of the leading causes of death for adults in the United States, with few therapeutics capable of preventing or slowing disease progression. The disordered nature of Aβ poses significant challenges for small-molecule drug design, largely associated with characterizing its conformational ensemble with atomistic resolution. Consequently, identifying targetable subpopulations of Aβ monomers has been inefficient with current experimental techniques. To address these challenges, we performed molecular dynamics (MD) simulations of the Aβ 10-35 fragment with the Drude polarizable force field (FF) and the weighted ensemble simulation toolkit with parallelization (WESTPA) software. The Drude FF provides a more robust representation of the electrostatic forces governing the conformational dynamics of the Aβ monomer. Additionally, the weighted ensemble approach enables enhanced sampling of rare conformational states by efficiently overcoming large free-energy barriers, facilitating sampling of conformational subpopulations that are inaccessible via conventional MD simulations. Our simulations revealed a broad range of Aβ conformations with varying probabilities of occurrence. These conformations were further analyzed in terms of secondary structure and electronic properties, with a particular emphasis on induced dipole effects. The identification and characterization of distinct Aβ subpopulations provide valuable insights into the structural heterogeneity of the Aβ monomer. This work has implications for the rational design of small-molecule therapeutics capable of interacting with multiple Aβ conformations.
Goodberlet et al. (Sun,) studied this question.