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Targeting Unoccupied Surfaces on Protein-Protein Interfaces.

David RooklinAshley E ModellHaotian LiViktoriya BerdanParamjit S AroraYingkai Zhang
Published in: Journal of the American Chemical Society (2017)
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.
Keyphrases
  • protein protein
  • small molecule
  • molecular dynamics simulations
  • amino acid
  • wild type
  • molecular docking
  • single molecule
  • escherichia coli
  • cystic fibrosis
  • drug delivery
  • neural network