Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 17, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2024324118
Keywords
bacterial RNA polymerase; Markov State Model; transcription initiation
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Funding
- Hong Kong Research Grant Council [16303919, 16307718, AoE/P-705/16, AoE/M-09/12, T13-605/18-W]
- Hong Kong Innovation and Technology Commission [ITCPD/17-9, ITC-CNERC14SC01]
- King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research [FCC/1/1976-23, FCC/1/1976-26, URF/1/4098-01-01, REI/1/0018-01-01]
- Hong Kong Research Grant Council Collaborative Research Fund [C6021-19EF]
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The study elucidated the dynamics of Thermus aquaticus holoenzyme's gate opening using a quasi-Markov State Model, revealing the differential roles of beta-lobe and clamp in DNA loading and the mechanism by which Myxopyronin inhibits clamp opening. Additionally, a critical role of beta-lobe in DNA loading was uncovered, presenting an opportunity for the development of antibiotics targeting this region of RNAP. The study also demonstrated the potential of quasi-Markov State Models in studying biomolecular dynamics based on generalized master equation formalism.
To initiate transcription, the holoenzyme (RNA polymerase [RNAP] in complex with sigma factor) loads the promoter DNA via the flexible loading gate created by the clamp and beta-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, beta-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 beta-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 beta-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.
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