TCBG Seminar

Multiscaling the CRISPR-Cas Revolution from Gene Editing to Viral Detection

Professor Giulia Palermo
Department of Bioengineering and Chemistry
University of California Riverside
Riverside, CA

Monday, January 24, 2022
3:00 pm (CT)


CRISPR is synonymous with a transformative genome editing technology that is innovating basic and applied sciences. I will report about the use of computational approaches to clarify the molecular basis and the gene-editing function of CRISPR-Cas9 and newly discovered CRISPR systems that are emerging as powerful tools for viral detection, including the SARS-CoV-2 coronavirus. We have implemented a multiscale approach, which combines classical molecular dynamics (MD) and enhanced sampling techniques, ab-initio MD, mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approaches and constant pH MD (CpH MD), as well as cryo-EM fitting tools and graph theory derived analysis methods, to reveal the mechanistic basis of nucleic acid binding, catalysis, selectivity, and allostery in CRISPR systems. Using a Gaussian accelerated MD method and the Anton-2 supercluster we determined the conformational activation of CRISPR-Cas9 and the selectivity mechanism against off-target sequences. By applying network models graph theory, we have characterized a mechanism of allosteric regulation, transferring the information of DNA binding to the catalytic sites for cleavages. This mechanism is now being probed in novel Anti-CRISPR proteins, forming multi- mega Dalton complexes with the CRISPR enzymes and used for gene regulation and control. CpH MD simulations have been combined with ab-initio MD and a mixed QM/MM approach to establish the catalytic mechanism of DNA cleavage. Finally, by using multi-microsecond MD simulations we have recently probed a mechanism of DNA-induced of activation in the Cas12a enzyme, which underlies the detection of viral genetic elements, including the SARS-CoV-2 coronavirus. Overall, our outcomes contribute to the mechanistic understanding of CRISPR- based gene-editing technologies, providing information that is critical for the development of improved gene-editing tools for biomedical applications.

Please click the link below to join the webinar: pwd=MU8zTVdNK1Q2aDkydkVsZTd6TzhxUT09 Password: 163330 Location : Hybrid: Zoom link or 3269 Beckman Institute

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