ArticlePLoS computational biology2016
A Biophysical Model of CRISPR/Cas9 Activity for Rational Design of Genome Editing and Gene Regulation.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed.
- Mesoscopic Calculation of Single Mismatches in RNA/DNA Hybrids: Strong Hydrogen Bonds of dTrG Affect CRISPR Off-Target Binding.The journal of physical chemistry. B · 2026Article
- Improvement of chicken genome editing efficiency in vitro using ribonucleoprotein-mediated CRISPR/Cas9 delivery.Journal of animal science and biotechnology · 2026Article
- Operating CRISPR/Cas12a in a complex nucleic acid sequence background.Nucleic acids research · 2026Article
- Non-clinical safety considerations on genome editing using the CRISPR/Cas system.Genes & diseases · 2026Review
- Synthetic Biology of Plants and Microbes for Agriculture, Environment, and Future Applications.Chemical reviews · 2026Review
- Better data for better predictions: data curation improves deep learning for sgRNA/Cas9 prediction.PeerJ · 2026Article
- Distribution of Genetic Determinants Associated with CRISPR-Cas Systems and Resistance to Antibiotics in the Genomes of Archaea and Bacteria.Microorganisms · 2025Article
- A generalizable Cas9/sgRNA prediction model using machine transfer learning with small high-quality datasets.Nature communications · 2023Article
- Bacteriophage strategies for overcoming host antiviral immunity.Frontiers in microbiology · 2023Review
- Structure- and Content-Dependent Efficiency of Cas9-Assisted DNA Cleavage in Genome-Editing Systems.International journal of molecular sciences · 2022Article
- Allele-Specific Disruption of a CommonGenes · 2022Article
- Thermodynamic Swings: How Ideal Complex of Cas9-RNA/DNA Forms.International journal of molecular sciences · 2022Article
- Antispacer peptide nucleic acids for sequence-specific CRISPR-Cas9 modulation.Nucleic acids research · 2022Article
- Microfluidic tool for rapid functional characterization of CRISPR complexes.New biotechnology · 2022Article
- Systematic decomposition of sequence determinants governing CRISPR/Cas9 specificity.Nature communications · 2022Article
- Review
- RGEN-seq for highly sensitive amplification-free screen of off-target sites of gene editors.Scientific reports · 2021Article
- crRNA complementarity shifts endogenous CRISPR-Cas systems between transcriptional repression and DNA defense.RNA biology · 2021Article
- The novel anti-CRISPR AcrIIA22 relieves DNA torsion in target plasmids and impairs SpyCas9 activity.PLoS biology · 2021Article
- Bacterial resistance to CRISPR-Cas antimicrobials.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ability to precisely modify genomes and regulate specific genes will greatly accelerate several medical and engineering applications. The CRISPR/Cas9 (Type II) system binds and cuts DNA using guide RNAs, though the variables that control its on-target and off-target activity remain poorly characterized. Here, we develop and parameterize a system-wide biophysical model of Cas9-based genome editing and gene regulation to predict how changing guide RNA sequences, DNA superhelical densities, Cas9 and crRNA expression levels, organisms and growth conditions, and experimental conditions collectively control the dynamics of dCas9-based binding and Cas9-based cleavage at all DNA sites with both canonical and non-canonical PAMs. We combine statistical thermodynamics and kinetics to model Cas9:crRNA complex formation, diffusion, site selection, reversible R-loop formation, and cleavage, using large amounts of structural, biochemical, expression, and next-generation sequencing data to determine kinetic parameters and develop free energy models. Our results identify DNA supercoiling as a novel mechanism controlling Cas9 binding. Using the model, we predict Cas9 off-target binding frequencies across the lambdaphage and human genomes, and explain why Cas9's off-target activity can be so high. With this improved understanding, we propose several rules for designing experiments for minimizing off-target activity. We also discuss the implications for engineering dCas9-based genetic circuits.
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Registered trials
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 OpenQuestion graph.