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Modeling Ligands into Maps Derived from Electron Cryomicroscopy
Published on: July 19, 2024
Conformational transitions upon ligand binding: holo-structure prediction from apo conformations
Daniel Seeliger1, Bert L de Groot
1Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
Plos Computational Biology
|January 13, 2010
Summary
This study introduces a novel computational method to predict protein-ligand complex structures using only the unbound protein structure and ligand information. This approach aids structure-based drug design when bound structures are unavailable.
Area of Science:
- Computational biology
- Structural biology
- Drug discovery
Background:
- Protein-ligand complex structures are crucial for biological function and drug design.
- Experimental structure determination is time-consuming and costly.
- Current computational docking methods struggle with significant receptor flexibility.
Purpose of the Study:
- To develop a computational method for predicting protein-ligand complex structures.
- To enable structure-based drug design when only unbound (apo) protein structures are available.
Main Methods:
- The method utilizes the apo protein structure, the small-molecule ligand, and the radius of gyration of the holo structure.
- Applied to ten protein systems exhibiting large conformational changes upon ligand binding.
Main Results:
- Achieved high accuracy in predicting receptor models (within 1.6 Å backbone RMSD).
- Successfully predicted near-native ligand binding poses in 8 out of 10 cases.
- Demonstrated applicability to proteins with significant structural rearrangements (up to 7.1 Å RMSD).
Conclusions:
- The presented method effectively models protein-ligand complexes even with significant receptor flexibility.
- This approach facilitates structure-based drug design for challenging cases lacking experimental bound structures.
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