De novo design of a homo-trimeric amantadine-binding protein

Jooyoung Park, Brinda Selvaraj, Andrew C McShan, Scott E Boyken, Kathy Y Wei, Gustav Oberdorfer, William DeGrado, Nikolaos G Sgourakis, Matthew J Cuneo, Dean Aa Myles, David Baker

Research output: Contribution to journalArticlepeer-review


The computational design of a symmetric protein homo-oligomer that binds a symmetry-matched small molecule larger than a metal ion has not yet been achieved. We used de novo protein design to create a homo-trimeric protein that binds the C3 symmetric small molecule drug amantadine with each protein monomer making identical interactions with each face of the small molecule. Solution NMR data show that the protein has regular three-fold symmetry and undergoes localized structural changes upon ligand binding. A high-resolution X-ray structure reveals a close overall match to the design model with the exception of water molecules in the amantadine binding site not included in the Rosetta design calculations, and a neutron structure provides experimental validation of the computationally designed hydrogen-bond networks. Exploration of approaches to generate a small molecule inducible homo-trimerization system based on the design highlight challenges that must be overcome to computationally design such systems.

Original languageEnglish
Article numbere47839
Publication statusPublished - 19 Dec 2019


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