ABSTRACT
The toxic component of amyloid is not the mature fiber but a soluble prefibrillar intermediate. It has been proposed, from molecular dynamics simulations, that the precursor is composed of alpha sheet, which converts into the beta sheet of mature amyloid via peptide plane flipping. alpha sheet, not seen in proteins, occurs as isolated stretches of polypeptide. We show that the alpha- to beta sheet transition can occur by the flipping of alternate peptide planes. The flip can be described as alphaRalphaL<-->betabeta. A search conducted within sets of closely related protein crystal structures revealed that these flips are common, occurring in 8.5% of protein families. The average "alphaL" conformation found is in an adjacent and less populated region of the Ramachandran plot, as expected if the flanking peptide planes, being hydrogen bonded, are restricted in their movements. This work provides evidence for flips allowing direct alpha- to beta sheet interconversion.
