2027-143-7

Stapled Peptide Design with Cofolding

Vedoucí práce: Dr. Wim Dehaen

Konzultant: Dr. Martin Šícho

Podstata a cíl práce

Stapled peptides are engineered peptides in which nonadjacent amino acid residues are covalently linked (“stapled”) through non-peptidic chemical reactions such as alkene metathesis or Huisgen cycloaddition. This covalent constraint increases peptide rigidity, stabilizes specific conformations, and enables efficient mimicry of protein secondary structures, even in relatively short peptides. Additionally, stapling makes the peptide more resistant against proteolytic degradation and can increase cell penetration. Recent advances in deep learning-based structure prediction now allow accurate modeling not only of proteins but also of modified peptides and other molecular modalities. These developments make it possible to computationally evaluate and optimize stapled peptide designs, transforming an initial unstapled sequence into an optimally preorganized stapled variant through iterative modeling. The goal of this project is, given an input peptide, to identify optimal stapling strategies while maintaining the native binding conformation. The outcome should demonstrate to which extent cofolding with structural evaluation can guide the design of stabilized peptide binders.

Náplň činnosti studenta

- Review the literature on stapled peptides and modern cofolding methods. - Set up and run state-of-the-art all-atom cofolding calculations (e.g., Boltz-2) to predict stapled peptide structures. - Evaluate predicted structures using backbone RMSD and related geometric metrics. The suitability of these metrics will be evaluated using known stapled peptide systems. - Apply an optimization workflow using existing stapling strategies to a selected peptide binder, proposing one or more designs that enhance structural preorganization.

Doplňující informace

Místo řešení: Ústav informatiky a chemie (143)

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