ArticleeLife2022
Ligand binding remodels protein side-chain conformational heterogeneity.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed.
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- GAMT-GINE: A Graph Isomorphism Network Integrating Continuous Spatial Awareness and Multi-Task Learning for Protein-Ligand Binding Affinity Prediction.International journal of molecular sciences · 2026Article
- PocketMaster provides a flexible and automated tool for analyzing, clustering, and visualizing structural diversity in protein pockets.Scientific reports · 2026Article
- Beyond the canonical: The role of post-transcriptional regulation in drug-target interaction prediction.PLoS computational biology · 2026Article
- In-Depth Molecular Dynamics Simulations Reveal Ligand-Induced Modulations of the HSPA8-SARS-CoV-2 Spike Protein Interaction.International journal of molecular sciences · 2026Article
- Differential oxidation of surimi actomyosin by malondialdehyde and heme: spectroscopy and molecular simulation.NPJ science of food · 2026Article
- Clove Essential Oil as an Antifungal Agent and Putative Dual-Action Antifungal Mechanism: Experimental Validation and Computational Insights into Orthosteric and Allosteric Modulation of Chitin Synthase I inMolecules (Basel, Switzerland) · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Mapping functional dynamics hotspots for protein engineering with NMR peak intensity analysis.Protein engineering, design & selection : PEDS · 2026Article
- All-atom molecular dynamics simulation of Cyclophilin A in complex with Sanglifehrin A.PloS one · 2026Article
- Crystallographic Ensembles Reveal the Structural Basis of Binding Entropy in SARS-CoV2 Macrodomain.bioRxiv : the preprint server for biology · 2025Article
- The inhibitory activities of two compounds fromPlant signaling & behavior · 2025Article
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- Sparse networks of conformational fluctuations communicate signals within proteins.bioRxiv : the preprint server for biology · 2025Article
- Conformational Dynamics of the Active Site Loop in Dihydroorotase Highlighting the Limitations of Loop-In Structures for Inhibitor Docking.International journal of molecular sciences · 2025Article
- Ten rules for a structural bioinformatic analysis.PLoS computational biology · 2025Article
- In Silico Design and Computational Elucidation of Hypothetical Resveratrol-Curcumin Hybrids as Potential Cancer Pathway Modulators.Pharmaceuticals (Basel, Switzerland) · 2025Article
- An experimental proxy of water displaceability for ligand discovery.Nature methods · 2025Article
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- TRPM8 Protein Dynamics Correlates with Ligand Structure and Cellular Function.Journal of the American Chemical Society · 2025Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors.
Funding
Abstract
While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent-exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decreases and relative hydrophobicity increases. Across a series of 13 inhibitor-bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from nuclear magnetic resonance studies suggesting that residual side-chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.
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