Characterization of prion fibril-binding dye molecules
Title: Characterization of prion fibril-binding dye molecules
DNr: SNIC 2015/1-44
Project Type: SNIC Medium Compute
Principal Investigator: Tamás Beke-Somfai <beke@chalmers.se>
Affiliation: Chalmers tekniska högskola
Duration: 2015-02-01 – 2016-03-31
Classification: 10402 10407 10601
Keywords:

Abstract

Prion disease related fibrils are peptide or polypeptide aggregates that have been extensively studied due to their association with a variety of diseases, and due to their general similarity to Alzheimer's or Parkinson's disease. When the key native proteins misfold and form self-assembled, insoluble aggregates, these plaques accumulate in different organs or tissues. The structure of amyloid fibrils has been found to be composed of beta-sheet rich motifs, which are oriented perpendicular to the long fibril axis. The fibrils themselves are nonbranching and can be up to several micrometers long with a width between 8 and 10 nm. Although prion and amyloid fibrils are mainly associated with neurodegenerative diseases, other proteins not related to such diseases have been found to form fibrils too. It is only recently becoming widely accepted that potentially any protein could form amyloid fibrils under specific conditions and that fibril formation is an intrinsic property of the polypeptide backbone. Extensive characterization of amyloid fibrils has been made using various spectroscopy and microscopy techniques. An often exploited method for spectroscopic determination of fibril formation is to use of certain dye molecules. These dyes are of particular interest because of their distinct spectral changes when bound to the amyloid fibrils. However, the molecular orientation of the dye molecules on the formed fibril structures is a subject to debate and theoretical calculations are needed to confirm spectroscopically observed changes and to connect these to the well-defined structural orientation of the dye molecules on the fibrils. Recently we have showed that indeed such an approach could provide valuable information which aids interpretation of the experimental results and thus contributes significantly to understanding the structural basis of amyloid fibrils.[1] Also, we have initiated investigation of a set of sensitive dyes binding to other fibrils, such as the ones found in prion diseases. These projects require theoretical characterization with Quantum Mechanics/Molecular Mechanics calculations combined with a set of Time Dependent Density Functional Theory calculations on the photophysical properties of the dyes bound to the fibrils. Recently we have managed to achieve significant advances in understanding the structural properties of these fibrils by combining QM, QM/MM calculations using different environments, and Linear Dichroism studies on mutat prion fibrils. This project is performed in collaboration with the group of Prof. Susan Lindquist (MIT). The calculation part of the project is the continuation of our previous simulation studies performed on Triolith [2]. [1] K., Catherine, T. Beke-Somfai, B. Norden, Michler's Hydrol Blue: A Sensitive Probe for Amyloid Fibril Detection, Biochemistry, 2011, 50, 3451-3461. [2] 2) A. Reymer, Frederick, K., S. Rocha, T. Beke-Somfai, C. C. Kitts, S. Lindquist, B. Nordén: Orientation of aromatic residues in amyloid cores: Structural insights into prion fiber diversity Proc. Natl. Acad. Sci., U.S.A., 2014, 111, 17158-17163