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    Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model.

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    Maintext_PNAS_revision_circulated_Xin.pdf
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    Type
    Article
    Authors
    Unarta, Ilona Christy
    Cao, Siqin
    Kubo, Shintaroh
    Wang, Wei
    Cheung, Peter Pak-Hang
    Gao, Xin cc
    Takada, Shoji
    Huang, Xuhui
    KAUST Department
    Computational Bioscience Research Center (CBRC)
    Computer Science Program
    Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division
    Structural and Functional Bioinformatics Group
    KAUST Grant Number
    FCC/1/1976-23
    FCC/1/1976-26
    REI/1/0018-01-01
    URF/1/4098-01-01
    Date
    2021-04-21
    Online Publication Date
    2021-04-21
    Print Publication Date
    2021-04-27
    Embargo End Date
    2021-10-22
    Permanent link to this record
    http://hdl.handle.net/10754/668915
    
    Metadata
    Show full item record
    Abstract
    To initiate transcription, the holoenzyme (RNA polymerase [RNAP] in complex with σ factor) loads the promoter DNA via the flexible loading gate created by the clamp and β-lobe, yet their roles in DNA loading have not been characterized. We used a quasi-Markov State Model (qMSM) built from extensive molecular dynamics simulations to elucidate the dynamics of Thermus aquaticus holoenzyme’s gate opening. We showed that during gate opening, β-lobe oscillates four orders of magnitude faster than the clamp, whose opening depends on the Switch 2’s structure. Myxopyronin, an antibiotic that binds to Switch 2, was shown to undergo a conformational selection mechanism to inhibit clamp opening. Importantly, we reveal a critical but undiscovered role of β-lobe, whose opening is sufficient for DNA loading even when the clamp is partially closed. These findings open the opportunity for the development of antibiotics targeting β-lobe of RNAP. Finally, we have shown that our qMSMs, which encode non-Markovian dynamics based on the generalized master equation formalism, hold great potential to be widely applied to study biomolecular dynamics.
    Citation
    Unarta, I. C., Cao, S., Kubo, S., Wang, W., Cheung, P. P.-H., Gao, X., … Huang, X. (2021). Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model. Proceedings of the National Academy of Sciences, 118(17), e2024324118. doi:10.1073/pnas.2024324118
    Sponsors
    X.H. was supported by the Hong Kong Research Grant Council (16303919, 16307718, AoE/P-705/16, AoE/M-09/12, and T13-605/18-W) and the Hong Kong Innovation and Technology Commission (ITCPD/17-9 and ITC-CNERC14SC01). X.G. was supported by the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research under Awards FCC/1/1976-23, FCC/1/1976-26, URF/1/4098-01-01, and REI/1/0018-01-01. This research made use of the computing resources of the Supercomputing Laboratory at KAUST and the X-GPU cluster supported by the Hong Kong Research Grant Council Collaborative Research Fund C6021-19EF.
    Journal
    Proceedings of the National Academy of Sciences
    DOI
    10.1073/pnas.2024324118
    PubMed ID
    33883282
    Additional Links
    http://www.pnas.org/lookup/doi/10.1073/pnas.2024324118
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.2024324118
    Scopus Count
    Collections
    Articles; Structural and Functional Bioinformatics Group; Computer Science Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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