Depletion of Water Molecules Near the End Stage of Steric Zipper Formation

Steric zipper refers to a structural motif where the residues of two neighboring beta-sheet layers are tightly interdigitated. Recently, steric zippers have been proposed as the fundamental structural units of amyloid fibrils. The steric zipper formed by polypeptides containing the palindromic sequence AGAAAAGA may have considerable biological relevance because the fragment AGAAAAGA is highly conserved in prion proteins of different species. The fibril core formed by AGAAAAGA has a distinctive structural feature that the distance between two interdigitated beta-sheet layers is comparable to the inter-strand distance of the individual beta sheet. In this work, the amyloid fibrils formed by the polypeptides of PrP(113-127), viz. Ac-AGAAAAGAVVGGLGG-NH2, are taken as the model compound for the solid-state NMR study of the formation of steric zipper. Near the end stage of the zipper formation, the NMR data show that there is a layer of water molecules trapped in between the two closely stacking -sheet layers. The zipper formation is completed upon the depletion of the water molecules between the interdigitated -sheet layers. On the basis of the NMR measurements and molecular dynamics simulations, we suggest that the residues A118 of the two neighboring beta sheets would first come into contact upon the zipper formation.