De novo design of modular peptide-binding proteins by superhelical matching

Kejia Wu, Hua Bai, Ya-Ting Chang, Rachel Redler, Kerrie E. McNally, William Sheffler, T. J. Brunette, Derrick R. Hicks, Tomos E. Morgan, Tim J. Stevens, Adam Broerman, Inna Goreshnik, Michelle DeWitt, Cameron M. Chow, Yihang Shen, Lance Stewart, Emmanuel Derivery (), Daniel Adriano Silva (), Gira Bhabha, Damian C. Ekiert and David Baker ()
Additional contact information
Kejia Wu: University of Washington
Hua Bai: University of Washington
Ya-Ting Chang: New York University School of Medicine
Rachel Redler: New York University School of Medicine
Kerrie E. McNally: MRC Laboratory of Molecular Biology
William Sheffler: University of Washington
T. J. Brunette: University of Washington
Derrick R. Hicks: University of Washington
Tomos E. Morgan: MRC Laboratory of Molecular Biology
Tim J. Stevens: MRC Laboratory of Molecular Biology
Adam Broerman: University of Washington
Inna Goreshnik: University of Washington
Michelle DeWitt: University of Washington
Cameron M. Chow: University of Washington
Yihang Shen: Carnegie Mellon University
Lance Stewart: University of Washington
Emmanuel Derivery: MRC Laboratory of Molecular Biology
Daniel Adriano Silva: University of Washington
Gira Bhabha: New York University School of Medicine
Damian C. Ekiert: New York University School of Medicine
David Baker: University of Washington

Nature, 2023, vol. 616, issue 7957, 581-589

Abstract: Abstract General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing peptide-binding proteins is challenging, as most peptides do not have defined structures in isolation, and hydrogen bonds must be made to the buried polar groups in the peptide backbone1–3. Here, inspired by natural and re-engineered protein–peptide systems4–11, we set out to design proteins made out of repeating units that bind peptides with repeating sequences, with a one-to-one correspondence between the repeat units of the protein and those of the peptide. We use geometric hashing to identify protein backbones and peptide-docking arrangements that are compatible with bidentate hydrogen bonds between the side chains of the protein and the peptide backbone12. The remainder of the protein sequence is then optimized for folding and peptide binding. We design repeat proteins to bind to six different tripeptide-repeat sequences in polyproline II conformations. The proteins are hyperstable and bind to four to six tandem repeats of their tripeptide targets with nanomolar to picomolar affinities in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including ladders of hydrogen bonds from protein side chains to peptide backbones. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating peptide sequences and for disordered regions of native proteins.

Date: 2023
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DOI: 10.1038/s41586-023-05909-9

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