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Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1
Name
nihms-1519568.pdf
Description
Accepted version
Size
1.32 MB
Format
Adobe PDF
Checksum (MD5)
af688fbe8acd47741505efea18b32772
Journal
Structure
Publisher
Elsevier BV
Citation
"Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1." Structure, 27 (4).
Version
Author's final manuscript
Abstract
© 2019 Elsevier Ltd Understanding the relationship between protein sequence and structure well enough to design new proteins with desired functions is a longstanding goal in protein science. Here, we show that recurring tertiary structural motifs (TERMs) in the PDB provide rich information for protein-peptide interaction prediction and design. TERM statistics can be used to predict peptide binding energies for Bcl-2 family proteins as accurately as widely used structure-based tools. Furthermore, design using TERM energies (dTERMen) rapidly and reliably generates high-affinity peptide binders of anti-apoptotic proteins Bfl-1 and Mcl-1 with just 15%–38% sequence identity to any known native Bcl-2 family protein ligand. High-resolution structures of four designed peptides bound to their targets provide opportunities to analyze the strengths and limitations of the computational design method. Our results support dTERMen as a powerful approach that can complement existing tools for protein engineering.
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
10.1016/J.STR.2019.01.008
