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Structure. 2019 Apr 2;27(4):606-617.e5. doi: 10.1016/j.str.2019.01.008. Epub 2019 Feb 14.

Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1.

Author information

1
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA.
3
Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA; Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, NH 03755, USA; Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, USA. Electronic address: gevorg.grigoryan@dartmouth.edu.
4
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Center for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: keating@mit.edu.

Abstract

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.

KEYWORDS:

BH3 motif; Bcl-2 proteins; apoptosis; inhibitor; interaction specificity; protein-protein interactions; structure-based design; tertiary motif

PMID:
30773399
PMCID:
PMC6447450
[Available on 2020-04-02]
DOI:
10.1016/j.str.2019.01.008

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