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Updated: Dec 10, 2025

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
A defined structural unit enables de novo design of small-molecule-binding proteins
Nicholas F Polizzi1, William F DeGrado1
1Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA. nicholas.polizzi@ucsf.edu william.degrado@ucsf.edu.
Abstract:
The de novo design of proteins that bind highly functionalized small molecules represents a great challenge. To enable computational design of binders, we developed a unit of protein structure-a van der Mer (vdM)-that maps the backbone of each amino acid to statistically preferred positions of interacting chemical groups. Using vdMs, we designed six de novo proteins to bind the drug apixaban; two bound with low and submicromolar affinity. X-ray crystallography and mutagenesis confirmed a structure with a precisely designed cavity that forms favorable interactions in the drug-protein complex. vdMs may enable design of functional proteins for applications in sensing, medicine, and catalysis.
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