4.6 Article

Functionalization of a symmetric protein scaffold: Redundant folding nuclei and alternative oligomeric folding pathways

Journal

PROTEIN SCIENCE
Volume 31, Issue 5, Pages -

Publisher

WILEY
DOI: 10.1002/pro.4301

Keywords

de novo design; heparin affinity; oligomerization; protein folding; protein stability

Funding

  1. Trefoil Therapeutics [RF02251]

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Successful protein design requires considering folding kinetics, stability thermodynamics, and biochemical functionality. The design can be simplified by separating it into two steps: initial design of a protein scaffold and subsequent functional mutation. This approach allows for broader functional adaptation.
Successful de novo protein design ideally targets specific folding kinetics, stability thermodynamics, and biochemical functionality, and the simultaneous achievement of all these criteria in a single step design is challenging. Protein design is potentially simplified by separating the problem into two steps: (a) an initial design of a protein scaffold having appropriate folding kinetics and stability thermodynamics, followed by (b) appropriate functional mutation-possibly involving insertion of a peptide functional cassette. This stepwise approach can also separate the orthogonal effects of the stability/function and foldability/function tradeoffs commonly observed in protein design. If the scaffold is a protein architecture having an exact rotational symmetry, then there is the potential for redundant folding nuclei and multiple equivalent sites of functionalization; thereby enabling broader functional adaptation. We describe such a scaffold and functional cassette design strategy applied to a beta-trefoil threefold symmetric architecture and a heparin ligand functionality. The results support the availability of redundant folding nuclei within this symmetric architecture, and also identify a minimal peptide cassette conferring heparin affinity. The results also identify an energy barrier of destabilization that switches the protein folding pathway from monomeric to trimeric, thereby identifying another potential advantage of symmetric protein architecture in de novo design.

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