ZURUECK HOCH VOR INHALT SUCHEN

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Proposing Institution

ICS-6: Structural Biochemistry, FZ Juelich
Project Manager

Dr. Bogdan Barz
Wilhelm-Johnen-Strasse
52425 Jülich
Abstract
Alzheimer's disease is the most common type of dementia and it manifests through the deterioration of cognitive domains related to memory. One of the proteins involved in AD is the amyloid beta (AB) protein whose aggregating behaviour and small oligomers are highly associated with neuronal death. The production of toxic oligomers has been recently shown to be greatly enhanced if fibrils are present in the environment. This type of biochemical reaction catalyzed by the fibril surface, known as secondary nucleation, leads to an exponential production of oligomers. However, little information is known about the details of the basic interactions between AB monomers and the fibril surface, including the energetics of monomer binding to the fibril or the conformations adopted by these monomers. Besides AB42, pyroglutamate AB3-42 (pEAB3-42) is one of the main constituents of amyloid plaques, more toxic than AB42, and was hypothesized to strongly attach to AB42 fibrils. In this project we aim at elucidating at atomistic detail the interactions between AB monomers and AB fibrils by combining enhanced all-atom molecular dynamics simulations with surface plasmon resonance experiments. We will focus on AB42 and pEAB3-42, the most toxic alloforms of AB found in amyloid plaques. Our main goal is to calculate the binding affinity and enthalpy of AB42 and pEAB3-42 monomers for AB42 fibrils from simulations and experiments and to resolve the structural conformation of the peptide during binding. Computationally, this will be achieved by calculating the temperature dependence of the binding affinity of monomers for fibrils using the non equilibrium sampling methods for calculating potentials of mean force in combination with Hamiltonian replica exchange simulations. We will target the fibril edges and the fibril sides and consider a recently derived AB42 fibril model that includes all amino acids.

Impressum, Conny Wendler