Ensemble docking for intrinsically disordered proteins
Anjali Dhar1, Thomas R Sisk1, Paul Robustelli1
1Dartmouth College, Department of Chemistry, Hanover, NH, 03755.
Biorxiv : the Preprint Server for Biology
|February 3, 2025
Summary
Intrinsically disordered proteins (IDPs) are key drug targets, but challenging for traditional design. New ensemble docking methods accurately predict small molecule binding affinities and mechanisms for IDPs like alpha-synuclein.
Area of Science:
- Biochemistry
- Computational Biology
- Drug Discovery
Background:
- Intrinsically disordered proteins (IDPs) are linked to numerous human diseases.
- IDPs lack stable 3D structures, making them difficult targets for conventional structure-based drug design.
- Targeting IDPs offers a promising avenue for novel therapeutic strategies.
Purpose of the Study:
- To develop computationally efficient ensemble docking approaches for predicting small molecule binding to IDPs.
- To characterize the dynamic and heterogeneous binding mechanisms of small molecules with IDPs at atomic resolution.
- To validate the predictive power of ensemble docking against experimental data.
Main Methods:
- Development of ensemble docking protocols tailored for intrinsically disordered proteins.
- Application of methods to predict relative binding affinities of small molecule ligands.
- Utilizing NMR spectroscopy for experimental validation of binding affinities.
- Comparison with long-timescale molecular dynamics simulations for binding mode analysis.
Main Results:
- Ensemble docking accurately predicted the relative binding affinities of alpha-synuclein ligands.
- The computational method generated conformational ensembles of ligand binding modes.
- Results showed remarkable agreement with experimentally validated molecular dynamics simulations.
- Demonstrated the capability to characterize dynamic binding mechanisms at atomic resolution.
Conclusions:
- Ensemble docking approaches show significant potential for predicting small molecule binding to IDPs.
- These computational methods can effectively characterize dynamic and heterogeneous binding mechanisms.
- The developed protocols may serve as valuable tools for accelerating IDP drug discovery campaigns.
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