Part:BBa_K4165007
WWW (Tau binding peptide)
Synthetic peptide used to bind to the aggregations of misfolded tau protein (BBa_K4165009) and toxic Amyloid beta plaques (BBa_K4165005).
Usage and Biology
WWW peptide is designed to inhibit the fibrilization of tau which is one of the main drivers of Alzheimer’s disease and other types of dementia. PHF* (VQIINK) is the site that derives the aggregation, WWW can bind to PHF* in a means that can disrupt the interaction between the filaments and consequently reduce the aggregates. Accordingly, this peptide would be suitable to act as the targeting domain in our systems.
Sequence and Features
- 10COMPATIBLE WITH RFC[10]
- 12COMPATIBLE WITH RFC[12]
- 21COMPATIBLE WITH RFC[21]
- 23COMPATIBLE WITH RFC[23]
- 25COMPATIBLE WITH RFC[25]
- 1000COMPATIBLE WITH RFC[1000]
Dry Lab
Modeling
WWW peptide was modeled using AlphaFold2, App test, RosettaFold, and TrRosetta. the best model was obtained from AlphaFold2 ranking 6 out of 6 according to our QA parameters.
Figure 1.: Predicted 3D structure of Synthetic peptide WWW visualized by Pymol.
Docking
We docked the WWW peptide with the whole tau, paired helical filaments of tau (PHF) and (PHF*)
ΔG = -173.217
Figure 2.: Docked structure of WWW and whole tau designed by Galaxy docking tool visualized by Pymol.
ΔG = -8.45
Figure 3.: Docked structure of WWW and PHF* of tau designed by Galaxy docking tool visualized by Pymol.
ΔG = -8.255
Figure 4.: Docked structure of WWW and PHF of tau designed by Galaxy docking tool visualized by Pymol.
All of binding energies were calculated using prodigy tool.
Mathematical modeling
Transcription rate and translation rate under T7 promotor
the mathematical modeling was based on our code for the calculation of transcription and translation (you can find it in the code section) beside with the estimated results from the wet lab.
Figure 5.: this figure shows the results from the transcription and translation code showing the
variation of mRNA and protein concentrations with time compared with the wet lab results.
References
1. Goedert, M., & Spillantini, M. G. (2017). Propagation of Tau aggregates. Molecular Brain, 10. https://doi.org/10.1186/s13041-017-0298-7
2. Etienne, M. A., Edwin, N. J., Aucoin, J. P., Russo, P. S., McCarley, R. L., & Hammer, R. P. (2007). Beta-amyloid protein aggregation. Methods in molecular biology (Clifton, N.J.), 386, 203–225. https://doi.org/10.1007/1-59745-430-3_7
3. Seidler, P., Boyer, D., Rodriguez, J., Sawaya, M., Cascio, D., Murray, K., Gonen, T., & Eisenberg, D. (2018). Structure-based inhibitors of tau aggregation. Nature chemistry, 10(2), 170. https://doi.org/10.1038/nchem.2889
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