The conformational transition of the amyloid β-peptide (Aβ) from partially structured monomers to highly ordered β-sheet fibrils is central to the pathology of Alzheimer’s disease. The most toxic forms of Aβ are soluble, disordered oligomers, which arise after the release of Aβ from the membrane into the extracellular environment. As such, understanding the earliest events in the aggregation cascade, namely the unfolding of partially helical, monomeric Aβ, is of critical importance in understanding the progression of Alzheimer’s. Several genetic mutations exist that accelerate aggregation and lead to more severe clinical manifestations; many mutations are concentrated at positions 22 and 23 in the full-length Aβ sequence and alter the net charge of the peptide. We have performed polarizable molecular dynamics (MD) simulations of both full-length and truncated forms of the Aβ peptide, including wild-type (WT) and several mutated variants (D23N, E22G, E22K, and E22Q). Our previous study using the Drude polarizable force field to investigate an Aβ fragment indicated mutation-specific unfolding pathways underlying transitions from α-helix to disordered coil. Here, we expand upon those results with umbrella sampling simulations to quantify the folding free energy of each fragment. Simulations with the nonpolarizable CHARMM36m force field are unable to distinguish between the WT and mutant folding free energies, however the Drude polarizable force field yields subtle differences in the folding free energies for each. To characterize the influence of tertiary interactions on the unfolding of this peptide fragment, we have performed simulations of the full-length (42-residue) Aβ peptide starting from helical and disordered conformations. Our findings provide novel insights into monomeric Aβ secondary and tertiary structure as well as backbone dipole properties that drive conformational transitions that are only observable with a polarizable force field.<br/>

Influence of induced polarization on the dynamics and folding free energy of the amyloid β-peptide

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.