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Related Concept Videos

Protein-protein Interfaces02:04

Protein-protein Interfaces

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Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
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Related Experiment Video

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In-vivo Detection of Protein-protein Interactions on Micro-patterned Surfaces
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Targeting Unoccupied Surfaces on Protein-Protein Interfaces.

David Rooklin1, Ashley E Modell1, Haotian Li1

  • 1Department of Chemistry, New York University , New York, New York 10003, United States.

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|August 1, 2017
PubMed
Summary

We developed a computational design strategy using AlphaSpace to create peptidomimetic inhibitors that target protein-protein interactions by optimizing pocket occupation. This method successfully designed an inhibitor for the KIX/MLL target, demonstrating its potential for drug discovery.

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Area of Science:

  • Computational drug design
  • Protein-protein interaction inhibitors
  • Peptidomimetic chemistry

Background:

  • Targeting protein-protein interfaces (PPIs) with peptidomimetics is a key strategy for inhibitor design.
  • This approach relies on mimicking native protein motifs, specifically hot spot residues, which presents design challenges.
  • Identifying suitable pockets for inhibitor binding is crucial for optimizing efficacy.

Purpose of the Study:

  • To present a novel pocket-centric computational design strategy guided by AlphaSpace.
  • To identify targetable and unoccupied pockets near peptidomimetic motifs for inhibitor design.
  • To optimize inhibitor binding and pocket occupation across protein interfaces.

Main Methods:

  • Utilized AlphaSpace to represent pocket space as Alpha-clusters.
  • Employed a pocket-centric strategy to guide the selection of amino acid mutations (natural and non-natural).
  • Tested the strategy on the KIX/MLL PPI target, optimizing a helical motif within MLL.
  • Validated inhibitor efficacy using molecular dynamics simulations and fluorescence polarization assays.

Main Results:

  • Successfully identified high-quality pockets suitable for inhibitor design.
  • Designed and optimized a peptidomimetic inhibitor targeting the KIX/MLL interaction.
  • Demonstrated the efficacy of the designed inhibitor through computational and experimental validation.

Conclusions:

  • The AlphaSpace-guided, pocket-centric computational design strategy is effective for developing PPI inhibitors.
  • This approach enables optimization of pocket occupation for enhanced inhibitor performance.
  • The strategy holds promise for designing novel therapeutics against challenging PPI targets.