The human TAR DNA-binding protein 43 (TDP-43) is crucial for regulating cellular processes such as transcription, RNA splicing, and mRNA transport and translation. However, its abnormal cytoplasmic aggregation disrupts these functions and contributes to the development of many neurodegenerative diseases. The aim of this study is to design and evaluate cyclic peptide binders capable of modulating the TDP-43 aggregation. Using the AfDesign tool, we generated 84 cyclic peptide binders of varying lengths (10 to 13 amino acids). Analysis revealed 17 binders with pLDDT scores above 70, indicating stable conformation, and 43 binders with pAE scores below 10, suggesting strong binding affinity to the target protein. Further binding affinity analysis with PRODIGY confirmed these results, identifying binders with low dissociation constant. Molecular dynamics (MD) simulations indicated that peptide binders effectively delayed TDP-43 aggregation. However, permeability studies using Steered Molecular Dynamics (SMD) simulation showed that the designed binders had a low permeability coefficient (2.18x10-15 cm/sec), significantly lower than the benchmark for effective permeability. This highlights the need for further optimization to enhance the binders’ permeability. Future work will involve scaling up the design process, improving screening techniques, and employing advanced simulation methods to achieve better insights and more effective peptide binders.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-531419 |
| Date | January 2024 |
| Creators | Huang, Jinling |
| Publisher | Uppsala universitet, Institutionen för farmaci |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Student thesis, info:eu-repo/semantics/bachelorThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
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