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Exploring the Binding Mechanism and Dynamics of EndoMS/NucS to Mismatched dsDNA

School of Physics, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China
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Int. J. Mol. Sci. 2019, 20(20), 5142; https://doi.org/10.3390/ijms20205142
Received: 2 September 2019 / Revised: 3 October 2019 / Accepted: 12 October 2019 / Published: 17 October 2019
(This article belongs to the Section Biochemistry)
The well-known mismatch repair (MMR) machinery, MutS/MutL, is absent in numerous Archaea and some Bacteria. Recent studies have shown that EndoMS/NucS has the ability to cleave double-stranded DNA (dsDNA) containing a mismatched base pair, which suggests a novel mismatch repair process. However, the recognition mechanism and the binding process of EndoMS/NucS in the MMR pathway remain unclear. In this study, we investigate the binding dynamics of EndoMS/NucS to mismatched dsDNA and its energy as a function of the angle between the two C-terminal domains of EndoMS/NucS, through molecular docking and extensive molecular dynamics (MD) simulations. It is found that there exists a half-open transition state corresponding to an energy barrier (at an activation angle of approximately 80 ) between the open state and the closed state, according to the energy curve. When the angle is larger than the activation angle, the C-terminal domains can move freely and tend to change to the open state (local energy minimum). Otherwise, the C-terminal domains will interact with the mismatched dsDNA directly and converge to the closed state at the global energy minimum. As such, this two-state system enables the exposed N-terminal domains of EndoMS/NucS to recognize mismatched dsDNA during the open state and then stabilize the binding of the C-terminal domains of EndoMS/NucS to the mismatched dsDNA during the closed state. We also investigate how the EndoMS/NucS recognizes and binds to mismatched dsDNA, as well as the effects of K + ions. The results provide insights into the recognition and binding mechanisms of EndoMS/NucS to mismatched dsDNA in the MMR pathway. View Full-Text
Keywords: protein–DNA interactions; mismatch repair; EndoMS/NucS; molecular dynamics protein–DNA interactions; mismatch repair; EndoMS/NucS; molecular dynamics
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Zhang, Y.; Huang, S. Exploring the Binding Mechanism and Dynamics of EndoMS/NucS to Mismatched dsDNA. Int. J. Mol. Sci. 2019, 20, 5142.

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