On the Fibril Elongation Mechanism of the Prion Protein Fragment PrP106-126

Abstract

Mouse prion protein PrP106-126 is a peptide corresponding to the residues 107-127 of human prion protein. It has been shown that PrP106-126 can reproduce the main neuropathological features of prionrelated transmissible spongiform encephalopathies and can form amyloid-like fibrils in vitro. The conformational characteristics of PrP106-126 fibril have been investigated by electron microscopy, CD spectroscopy, NMR and molecular dynamics simulations. Recent researches have found out that PrP106-126 in water assumes a stable structure consisting of two parallel beta-sheets that are tightly packed against each other. In this work we perform molecular dynamics simulation to reveal the elongation mechanism of PrP106-126 fibril. Influenced by the edge strands of the fibril which already adopt beta-sheets conformation, single PrP106-126 peptide forms beta-structure and becomes a new element of the fibril. Under acidic condition, single PrP106-126 peptide adopts a much larger variety of conformations than it does under neural condition, which makes a peptide easier to be influenced by the edge strands of the fibril. However, acidic condition dose not largely affect the stability of PrP106-126 peptide fibril. Thus, the speed of fibril elongation can be dramatically increased by lowering the pH value of the solution. The pH value was adjusted by either changing the protonation state of the residues or adding hydronium ions (acidic solution) or hydroxyl ions (alkaline solution). The differences between these two approaches are analyzed here.