Thermodynamics and structural description of Amyloid-beta 1-42 and pyroglutamate-modified Amyloid-beta 3-42 peptides binding to fibrils.

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Alzheimer disease (AD) 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 molecular 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 binding affinity of monomers for fibrils using the umbrella sampling method 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. To calculate the binding enthalpy we will study the temperature dependence of the binding process from Arrhenius plots and vant Hoff analysis. Experimentally, the binding affinity will be calculated from fibril washing experiments and SPR measurements. The detachment of peptides from the fibril surface is expected to exhibit a combination of linear and exponential behaviours, specific to detachment from the fibril end and from the fibril surface, respectively. The amplitude of the exponential function for different monomer concentrations will lead to Langmuir adsorption isotherms, and thus the critical monomer concentration associated with the binding affinity for the fibril surface. Thus we will describe thoroughly for the first time, using both computational and experimental methods, the energetics and structure of AB42 and pEAB3-42 peptides binding to the fibrils.