Research Projects

Nature performs intricate protein origami and assembles nanostructures capable of performing diverse tasks. Designed protein assembly has lagged behind DNA origami due to the diversity of small interactions between proteins and protein-protein interactions. Mutations can have far-reaching effects, and designing protein-protein interfaces for assembly is computationally expensive and uncertain. A study on cysteine protease inhibitor (cystatin) protein revealed that domain-swapping, a process that stabilizes proteins, allows for dimerization. This discovery opens up the field of protein assembly through domain-swapping, which requires few loop mutations and stabilizes assemblies through the same interactions that stabilize monomeric proteins. The physico-chemical reasons behind loop mutations driving domain-swapping are unclear, but one hypothesis is that solvent-exposed hydrophobic residues in loop regions drive domain-swapping. The researchers plan to combine molecular dynamics simulations and experiments to quantify residue interactions and the structural context that promotes oligomerization. They also aim to understand the role of timing and rates in natural protein assembly using coarse-grained structure-based simulations. They hypothesize that some assemblies can form correctly at equilibrium when both binding and unbinding rates are high. Using 3D-domain-swapping to design protein assembly, the researchers plan to use loop mutations and tandem protein domains to create symmetric nanostructures and explore the use of both dimers and nanostructures in building functional materials.

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