3 years ago

Targeting Unoccupied Surfaces on Protein–Protein Interfaces

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

Publisher URL: http://dx.doi.org/10.1021/jacs.7b05960

DOI: 10.1021/jacs.7b05960

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