Biophysical Society Thematic Meeting | Trieste 2024

Emerging Theoretical Approaches to Complement Single-Particle Cryo-EM

Poster Abstracts

5-POS Board 5 REPRODUCTION OF TAU FIBRIL FORMATION USING COARSE-GRAINED MOLECULAR DYNAMICS SIMULATIONS AND VALIDATION VIA CRYOGENIC ELECTRON MICROSCOPY Thomas Fellmeth 2,3 ; Jozef Hritz 1,2 ; 1 Masaryk University, Department of Chemistry, Brno, Czech Republic 2 Masark University, Central European Institute of Technology, Brno, Czech Republic 3 Masaryk University, National Centre for Biomolecular Research, Brno, Czech Republic Tau is a well-known intrinsically disordered protein (IDP), found hyperphosphorylated in Alzheimer’s disease (AD) in human brains. Under pathological conditions, tau undergoes hyperphosphorylation, leading to tau fibrillation. [1] The most abundant forms of tau fibrils are the paired helical filaments (PHFs) and the straight filaments (SFs), which are structural polymorphes. Further tauopathies like Pick’s disease or Parkinson’s disease, show different disease-specific conformations of tau fibrils. [2] Molecular dynamics simulations can provide insights on the time-evolution of tau fibril formation on molecular level. The predicted fibril structures will then be validated using single-particle cryogenic electron microscopy (cryo-EM). All simulation will be performed on coarse-grained (CG) level of resolution because it allows to extend the lengths and time scale of the system by orders of magnitudes compared to all-atom simulations. [3] For tau fibril structure determination, cryo-EM is the method of choice, because it is a well-established high-resolution structural biology method that provides insights on near atomistic level. The importance of the choice of different CG force fields in combination with the water model was investigated. SIRAH was found to give a fair description of the conformational ensemble of monomeric tau and can accurately reproduce NMR data, such as the gyration radius. The collapsing nature of the CG force field is shown to be overcome by strengthening the water-protein interactions. The polarizable Martini force field for both, protein and water leads to less collapsed conformations. Analysis of the interaction surface of the PHF of AD indicates, that salt bridges between 331Lys and 338Glu play an important role for their stability. Furthermore, the effect of buffer conditions, especially the choice of the ions on the stability of both, the PHF and SF will be discussed. Understanding the mechanism of tau fibrillation is the key to understand the neurodegenerative process of AD and related tauopathies. The computational resources in IT4Innovations were granted by the Ministry of Education, Youth and Sports of the Czech Republic through the e-INFRA CZ (ID:90254). This project was supported by the Brno Ph.D. Talent Scholarship – funded by the Brno City Municipality, Czech Republic and by the European Union’s Horizon Europe 2020 program under the grant agreement No. 101087124 – ADDIT-CE. [1] E. M. Mandelkow and E. Mandelkow, Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Biol., 4:ea006247, 2012.[2] B. Falcon et al., Tau filaments from multiple cases of sporadic and inherited alzheimer’s disease adopt a common fold. Acta Neuropathol, 136(5):699–708, 2018.[3] P. Latham and B. Zhang, Unifying coarse-grained force fields for folded and disordered proteins. Current Opinion in Structural Biology, 72:63–70, 2022.

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