Targeting Unoccupied Surfaces on Protein-Protein Interfaces

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

Research output: Contribution to journalArticlepeer-review


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
Issue number44
StatePublished - Nov 8 2017

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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