Cooperative Dynamics Of Rec-Nuc Lobes Prime Cas12a For Dna Processing
BIOPHYSICAL JOURNAL(2021)
摘要
The CRISPR-Cas12a system is the basis of the DETECTR technology, which allows extraordinarily rapid detection of viruses including SARS-CoV-2 that is spreading across multiple countries. Here, a collective ensemble of multi-microsecond molecular dynamics is used to characterize the key dynamic determinants allowing nucleic acid processing in CRISPR-Cas12a. We show that DNA binding induces a switch in the conformational dynamics of Cas12a, which results in the activation of the peripheral REC2 and Nuc domains to enable cleavage of nucleic acids. The simulations reveal that large-amplitude motions of the Nuc domain could favor the conformational activation of the system toward DNA cleavages. in this process, the REC lobe plays a critical role. Accordingly, the joint dynamics of REC and Nuc shows the tendency to prime the conformational transition of the DNA target strand toward the catalytic site. Most notably, the highly coupled dynamics of the REC2 region and Nuc domain suggest that REC2 could act as a regulator of the Nuc function, similar to what was observed previously for the HNH domain in the CRISPR-associated nuclease Cas9. These mutual dynamics of REC and Nuc could be critical for the non-specific binding of DNA and thereby, for the underlying mechanistic functioning of the DETECTR technology. Overall, our outcomes advance our mechanistic understanding of CRISPR-Cas12a and provide a ground for novel engineering efforts aimed at improved genome editing and viral detection.
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关键词
dna,rec-nuc
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