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Ligand Binding Sites02:40

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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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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The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
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Accurate ligand-protein docking in CASP15 using the ClusPro LigTBM server.

Sergei Kotelnikov1,2, Ryota Ashizawa1,2, Konstantin I Popov3

  • 1Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, USA.

Proteins
|September 12, 2023
PubMed
Summary

Template-based ligand docking, like ClusPro ligTBM, proved highly effective in the CASP15 competition for predicting small molecule binding to protein targets. This approach, utilizing homology, outperformed direct docking on AlphaFold2 models.

Keywords:
AlphaFold2 modelsBRIKARD macrocycle modelingClusPro docking programFTMap protein mappingtemplate-based ligand docking

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Area of Science:

  • Computational biology
  • Structural bioinformatics
  • Drug discovery

Background:

  • The CASP15 competition focused on predicting small molecule-protein interactions.
  • Protein models were provided as amino acid sequences or generated by AlphaFold2.
  • Accurate ligand binding prediction is crucial for drug development.

Purpose of the Study:

  • To evaluate the performance of template-based ligand docking methods in CASP15.
  • To compare template-based docking with direct docking on AlphaFold2 models.
  • To identify effective strategies for ligand binding site prediction.

Main Methods:

  • Utilized ClusPro ligTBM, a template-based ligand docking program, for most targets.
  • Employed Glide for direct docking when templates were unavailable.
  • Required manual interventions and multiple templates for complex targets.

Main Results:

  • The ClusPro ligTBM server was a highly useful tool in the CASP15 ligand prediction category.
  • The research group ranked among the top five performing teams.
  • All top-performing groups successfully employed template-based docking methods.

Conclusions:

  • Template-based docking is a robust method for predicting ligand binding sites, even with AlphaFold2 models.
  • AlphaFold2 models, while accurate in backbone prediction, exhibit local differences challenging direct docking.
  • Homology-based docking effectively overcomes limitations associated with direct docking on predicted protein structures.