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A defined structural unit enables de novo design of small-molecule-binding proteins.

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.

SUBMITTER: Polizzi NF 

PROVIDER: S-EPMC7526616 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A defined structural unit enables de novo design of small-molecule-binding proteins.

Polizzi Nicholas F NF   DeGrado William F WF  

Science (New York, N.Y.) 20200901 6508

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 structu  ...[more]

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