Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 125, Issue 31, Pages 8787-8796Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.1c04528
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Funding
- High Performance Computing Center at Oklahoma State University through the National Science Foundation [OAC-1531128]
- National Science Foundation [ACI-1548562]
- San Diego Supercomputer Center Comet [CHE160008]
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Research has identified four structural states of RNA-nsp13 that exhibit different RNA-binding poses and characteristics, supporting the inchworm mechanism for ATP-dependent RNA translocation. Understanding these structures and mechanisms provides novel targets for the further development of antiviral therapeutics.
The COVID-19 pandemic has demonstrated the need to develop potent and transferable therapeutics to treat coronavirus infections. Numerous antiviral targets are being investigated, but nonstructural protein 13 (nsp13) stands out as a highly conserved and yet understudied target. Nsp13 is a superfamily 1 (SF1) helicase that translocates along and unwinds viral RNA in an ATP-dependent manner. Currently, there are no available structures of nsp13 from SARS-CoV-1 or SARS-CoV-2 with either ATP or RNA bound, which presents a significant hurdle to the rational design of therapeutics. To address this knowledge gap, we have built models of SARS-CoV-2 nsp13 in Apo, ATP, ssRNA and ssRNA+ATP substrate states. Using 30 mu s of a Gaussianaccelerated molecular dynamics simulation (at least 6 mu s per substrate state), these models were confirmed to maintain substrate binding poses that are similar to other SF1 helicases. A Gaussian mixture model and linear discriminant analysis structural clustering protocol was used to identify key structural states of the ATP-dependent RNA translocation mechanism. Namely, four RNA-nsp13 structures are identified that exhibit ATP-dependent populations and support the inchworm mechanism for translocation. These four states are characterized by different RNA-binding poses for motifs Ia, IV, and V and suggest a power stroke-like motion of domain 2A relative to domain 1A. This structural and mechanistic insight of nsp13 RNA translocation presents novel targets for the further development of antivirals.
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