De novo Design of a Homo-Trimeric

April 2, 2020
De novo Design of a Homo-Trimeric
Models derived from neutron diffraction data. (Left) ordered water molecules and hydrogen-bond network between the polar serine residues (Ser-71) and amantadine; (Right) Residues involved in the designed hydrogen-bond networks (black dashed lines) in the ABP complex.

Scientific Achievement

Experimental structure measurements validated the first computational design of a symmetric homo-oligomer that binds to a symmetry-matched small molecule. 

Significance and Impact

The designed homo-trimeric protein binds to the FDA-approved, small-molecule drug amantadine. This is a step towards the reuse of licensed drugs for new medical treatments.

Research Details

  • Computational methods employing RosettaDesign were employed for de novo design of the protein.
  • Nuclear magnetic resonance (NMR) verified the protein’s 3-fold symmetry
  • X-ray diffraction showed a close overall match of the structure to the design model.
  • Neutron diffraction verified that hydrogen bond networks correspond to the computational design. 

“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 A.A. Myles, David Baker,
eLIFE, 8, e47839 (2019). DOI: 10.7554/eLife.47839