ArticleWiley interdisciplinary reviews. Computational molecular science
Establishing the allosteric mechanism in CRISPR-Cas9.
Article in Wiley interdisciplinary reviews. Computational molecular science. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- A dynamically frustrated allosteric checkpoint consistent with conformational proofreading in CRISPR-Cas9.Nucleic acids research · 2026Article
- Molecular mechanisms and biotechnology applications of CRISPR-Cas12a.Nature reviews. Molecular cell biology · 2026Review
- A Computational Model for Nme1Cas9 HNH Activation Driven by Dynamic Interface Engineering at Residues S593 and W596.Biomolecules · 2026Article
- Chemical control of 2'-hydroxyl-dependent Cas9 target engagement enables CRISPR RNA ribose replacement.bioRxiv : the preprint server for biology · 2026Article
- And… cut! - how conformational regulation of CRISPR-Cas effectors directs nuclease activity.The Biochemical journal · 2025Review
- Design Rules for Expanding PAM Compatibility in CRISPR-Cas9 from the VQR, VRER and EQR variants.bioRxiv : the preprint server for biology · 2025Article
- Off-target interactions in the CRISPR-Cas9 Machinery: mechanisms and outcomes.Biochemistry and biophysics reports · 2025Review
- Article
- Exploring CRISPR-Cas9 HNH-Domain-Catalyzed DNA Cleavage Using Accelerated Quantum Mechanical Molecular Mechanical Free Energy Simulation.Biochemistry · 2025Article
- Flexibility in PAM Recognition Expands DNA Targeting in xCas9.bioRxiv : the preprint server for biology · 2025Article
- Graph theory approaches for molecular dynamics simulations.Quarterly reviews of biophysics · 2024Article
- Predicting Mutation-Induced Allosteric Changes in Structures and Conformational Ensembles of the ABL Kinase Using AlphaFold2 Adaptations with Alanine Sequence Scanning.International journal of molecular sciences · 2024Article
- CRISPR-Based Therapies: Revolutionizing Drug Development and Precision Medicine.Current gene therapy · 2024Review
- Putting CRISPR-Cas system in action: a golden window for efficient and precise genome editing for crop improvement.GM crops & food · 2023Review
- Differential Divalent Metal Binding by SpyCas9's RuvC Active Site Contributes to Nonspecific DNA Cleavage.The CRISPR journal · 2023Article
- Machines on Genes through the Computational Microscope.Journal of chemical theory and computation · 2023Review
- The Electronic Structure of Genome Editors from the First Principles.Electronic structure (Bristol, England) · 2023Article
- Full-Length Model of SaCas9-sgRNA-DNA Complex in Cleavage State.International journal of molecular sciences · 2023Article
- Disruption of electrostatic contacts in the HNH nuclease from a thermophilic Cas9 rewires allosteric motions and enhances high-temperature DNA cleavage.The Journal of chemical physics · 2022Article
- Emerging Methods and Applications to Decrypt Allostery in Proteins and Nucleic Acids.Journal of molecular biology · 2022Review
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4 authors.
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Abstract
Allostery is a fundamental property of proteins, which regulates biochemical information transfer between spatially distant sites. Here, we report on the critical role of molecular dynamics (MD) simulations in discovering the mechanism of allosteric communication within CRISPR-Cas9, a leading genome editing machinery with enormous promises for medicine and biotechnology. MD revealed how allostery intervenes during at least three steps of the CRISPR-Cas9 function: affecting DNA recognition, mediating the cleavage and interfering with the off-target activity. An allosteric communication that activates concerted DNA cleavages was found to led through the L1/L2 loops, which connect the HNH and RuvC catalytic domains. The identification of these "allosteric transducers" inspired the development of novel variants of the Cas9 protein with improved specificity, opening a new avenue for controlling the CRISPR-Cas9 activity. Discussed studies also highlight the critical role of the recognition lobe in the conformational activation of the catalytic HNH domain. Specifically, the REC3 region was found to modulate the dynamics of HNH by sensing the formation of the RNA:DNA hybrid. The role of REC3 was revealed to be particularly relevant in the presence of DNA mismatches. Indeed, interference of REC3 with the RNA:DNA hybrid containing mismatched pairs at specific positions resulted in locking HNH in an inactive "conformational checkpoint" conformation, thereby hampering off-target cleavages. Overall, MD simulations established the fundamental mechanisms underlying the allosterism of CRISPR-Cas9, aiding engineering strategies to develop new CRISPR-Cas9 variants for improved genome editing.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.