Conformations of peptides from microtubule repeat regions of intrinsically disordered protein tau

O. Cehlar^1,2, R. Skrabana^1,2, M. Novak¹

¹ Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 845 10 Bratislava, Slovakia

² Axon Neuroscience R&D Services SE, Dvorakovo Nabrezie 10, 811 02 Bratislava, Slovakia

ondrej.cehlar@savba.sk

Accumulation of intrinsically disordered protein tau in the form of insoluble aggregates is a common feature of neurodegenerative tauopathies. Monoclonal antibody DC8E8 is able to inhibit tau-tau interaction and therefore it holds promise for the immunotherapy of Alzheimer’s disease. Minimal epitope of DC8E8 represents amino acid motif HXPGGG that is present in each of the four microtubule binding repeats (MTBRs) of tau. The active vaccine based on the DC8E8 epitope peptide has successfully passed the phase 1 clinical trial [1].

We have performed 300 ns long molecular dynamics simulations of 18 amino acids containing tau peptides from all four MTBRs in NAMD program with CHARMM36m force field suitable for simulation of intrinsically disordered proteins [2]. We have compared the sampled conformations with the conformations of respective peptides observed by cryo-EM in filaments isolated from cases of Alzheimer’s disease and Pick’s disease [3, 4]. We have also measured FTIR spectra of tau peptides used for MD simulations and compared the results. Unravelling the unique mode of recognition of DC8E8 antibody and conformational biases of tau protein repeat regions can aid to reveal the hindered structural features of tau protein biology.

1. Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, Vince-Kazmerova Z, Katina S, Fialova L, Prcina M, et al., Lancet Neurology, 16, (2017), 123-134.

2. Huang, J., Rauscher, S., Nawrocki, G., Ran, T., Feig, M., de Groot, B. L., Grubmuller, H. & MacKerell, A. D., Nat Methods, 14, (2017), 71.

3. Fitzpatrick, A.W.P., Falcon, B., He, S., Murzin, A.G., Murshudov, G., Garringer, H.J., Crowther, R.A., Ghetti, B., Goedert, M., and Scheres, S.H.W., Nature, 547, (2017), 185-+.

4. Falcon, B., Zhang, W.J., Murzin, A.G., Murshudov, G., Garringer, H.J., Vidal, R., Crowther, R.A., Ghetti, B., Scheres, S.H.W., and Goedert, M., Nature, 561, (2018), 137-+.

This work was supported by the VEGA No. 2/0177/15. Calculations were performed in the Computing Centre of the Slovak Academy of Sciences using the supercomputing infrastructure acquired in project ITMS 26230120002 and 26210120002 (Slovak infrastructure for high-performance computing) supported by the Research & Development Operational Programme funded by the ERDF.