Targeting Unoccupied Surfaces on Protein-Protein Interfaces

David Rooklin, Ashley E. Modell, Haotian Li, Viktoriya Berdan, Paramjit Arora, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

The use of peptidomimetic scaffolds to target protein-protein interfaces is a promising strategy for inhibitor design. The strategy relies on mimicry of protein motifs that exhibit a concentration of native hot spot residues. To address this constraint, we present a pocket-centric computational design strategy guided by AlphaSpace to identify high-quality pockets near the peptidomimetic motif that are both targetable and unoccupied. Alpha-clusters serve as a spatial representation of pocket space and are used to guide the selection of natural and non-natural amino acid mutations to design inhibitors that optimize pocket occupation across the interface. We tested the strategy against a challenging protein-protein interaction target, KIX/MLL, by optimizing a single helical motif within MLL to compete against the full-length wild-type MLL sequence. Molecular dynamics simulation and experimental fluorescence polarization assays are used to verify the efficacy of the optimized peptide sequence.

Original languageEnglish (US)
Pages (from-to)15560-15563
Number of pages4
JournalJournal of the American Chemical Society
Volume139
Issue number44
DOIs
StatePublished - Nov 8 2017

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Membrane Proteins
Peptidomimetics
Proteins
Amino Acid Motifs
Fluorescence Polarization
Genetic Selection
Molecular Dynamics Simulation
Occupations
Scaffolds (biology)
Scaffolds
Peptides
Molecular dynamics
Amino acids
Assays
Amino Acids
Mutation
Fluorescence
Polarization
Computer simulation

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Targeting Unoccupied Surfaces on Protein-Protein Interfaces. / Rooklin, David; Modell, Ashley E.; Li, Haotian; Berdan, Viktoriya; Arora, Paramjit; Zhang, Yingkai.

In: Journal of the American Chemical Society, Vol. 139, No. 44, 08.11.2017, p. 15560-15563.

Research output: Contribution to journalArticle

Rooklin, David ; Modell, Ashley E. ; Li, Haotian ; Berdan, Viktoriya ; Arora, Paramjit ; Zhang, Yingkai. / Targeting Unoccupied Surfaces on Protein-Protein Interfaces. In: Journal of the American Chemical Society. 2017 ; Vol. 139, No. 44. pp. 15560-15563.
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