Understanding the Packing of Amyloidogenic Peptide Segments using Electronic Structure Calculations

Abstract

It has been proposed that antiparallel amyloid fibrils are more likely to fold into potentially toxic, transient morphologies as they are typically less stable than parallel fibrils. Recent studies of some amyloidogenic protein segments revealed that crystallize as antiparallel out-of-register β-strands, unlike most amyloid fibrils that fold into an in-register β-sheet packing. Therefore, it has been suggested that such arrangement may be responsible for the cytotoxicity in amyloid diseases. Interestingly, crystal structures of the amyloidogenic peptide segments NFGAILS and FGAILSS showed antiparallel zippers assembled into out-of-register and in-register sheets, respectively, even though they differ in only one amino acid at the termini. In this work, we use density functional theory (DFT) to elucidate the molecular mechanism driving their different crystallization patterns by investigating the differences in energetics and structure between them. Our results primarily show that the electrostatic potential (ESP) at the termini in the out-of-register peptide is significantly larger than in the in-register system. These findings may help to understand the underlying molecular phenomena dictating the toxicity of amyloid fibrils.