ArticleProceedings of the National Academy of Sciences of the United States of America2012
Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 143 papers.
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Who cites it
143 citing papers in PubMed.
- Uncovering hidden druggable sites: computational approaches to allosteric and cryptic pocket discovery-from molecular dynamics to AI.Journal of computer-aided molecular design · 2026Review
- Benchmarking AI Protein Structure Predictors Reveals a Persistent Bias in Multi-State Proteins.bioRxiv : the preprint server for biology · 2026Article
- Fold-Switching Proteins.Annual review of biophysics · 2026Review
- CryptoBank: A resource for the identification and prediction of cryptic sites in proteins.Science advances · 2026Article
- Article
- Decrypting cryptic pockets with physics-based simulations and artificial intelligence.Current opinion in structural biology · 2026Review
- Contact Cluster Modeling of Allosteric Communication in PDZ Domains.The journal of physical chemistry. B · 2026Review
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- Article
- Computational Ligand-Binding Site Prediction.Advances in experimental medicine and biology · 2026Review
- The Human Omnibus of Targetable Pockets.Journal of cheminformatics · 2025Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.Journal of molecular biology · 2025Review
- Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes.eLife · 2025Article
- From Concepts to Inhibitors: A Blueprint for Targeting Protein-Protein Interactions.Chemical reviews · 2025Review
- Fold-switching proteins.ArXiv · 2025Article
- SARS-CoV-2 Mpro Dihedral Angles Reveal Allosteric Signaling.Proteins · 2025Article
- Protein Catalysis Through Structural Dynamics: A Comprehensive Analysis of Energy Conversion in Enzymatic Systems and Its Computational Limitations.Pharmaceuticals (Basel, Switzerland) · 2025Review
- 'Intelligent' proteins.Cellular and molecular life sciences : CMLS · 2025Review
- Allostery and Evolution: A Molecular Journey Through the Structural and Dynamical Landscape of an Enzyme Super Family.Molecular biology and evolution · 2025Article
83 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors.
Funding
Abstract
Cryptic allosteric sites--transient pockets in a folded protein that are invisible to conventional experiments but can alter enzymatic activity via allosteric communication with the active site--are a promising opportunity for facilitating drug design by greatly expanding the repertoire of available drug targets. Unfortunately, identifying these sites is difficult, typically requiring resource-intensive screening of large libraries of small molecules. Here, we demonstrate that Markov state models built from extensive computer simulations (totaling hundreds of microseconds of dynamics) can identify prospective cryptic sites from the equilibrium fluctuations of three medically relevant proteins--β-lactamase, interleukin-2, and RNase H--even in the absence of any ligand. As in previous studies, our methods reveal a surprising variety of conformations--including bound-like configurations--that implies a role for conformational selection in ligand binding. Moreover, our analyses lead to a number of unique insights. First, direct comparison of simulations with and without the ligand reveals that there is still an important role for an induced fit during ligand binding to cryptic sites and suggests new conformations for docking. Second, correlations between amino acid sidechains can convey allosteric signals even in the absence of substantial backbone motions. Most importantly, our extensive sampling reveals a multitude of potential cryptic sites--consisting of transient pockets coupled to the active site--even in a single protein. Based on these observations, we propose that cryptic allosteric sites may be even more ubiquitous than previously thought and that our methods should be a valuable means of guiding the search for such sites.
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