Dynamics of spontaneous flipping of a mismatched base in DNA duplex.
DNA base flipping is a fundamental theme in DNA biophysics. The dynamics for a B-DNA base to spontaneously flip out of the double helix has significant implications in various DNA-protein interactions but are still poorly understood. The spontaneous base-flipping rate obtained previously via the imino proton exchange assay is most likely the rate of base wobbling instead of flipping. Using the diffusion-decelerated fluorescence correlation spectroscopy together with molecular dynamics simulations, we show that a base of a single mismatched base pair (T-G, T-T, or T-C) in a double-stranded DNA can spontaneously flip out of the DNA duplex. The extrahelical lifetimes are on the order of 10 ms, whereas the intrahelical lifetimes range from 0.3 to 20 s depending on the stability of the base pairs. These findings provide detailed understanding on the dynamics of DNA base flipping and lay down foundation to fully understand how exactly the repair proteins search and locate the target mismatched base among a vast excess of matched DNA bases.
Beijing National Laboratory for Molecular Sciences,State Key Laboratory for Structural Chemistry of Unstable and Stable Species,Biodynamic Optical Imaging Center,Department of Chemical Biology and.
Yandong
Y
Yin
Beijing National Laboratory for Molecular Sciences,Biodynamic Optical Imaging Center,Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and.
Lijiang
L
Yang
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.
Guanqun
G
Zheng
Beijing National Laboratory for Molecular Sciences,Biodynamic Optical Imaging Center,Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and.
Chan
C
Gu
Synthetic and Functional Biomolecules Center, Peking University, Beijing 100871, China; and.
Chengqi
C
Yi
Department of Chemical Biology andDepartment of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637Synthetic and Functional Biomolecules Center, Peking University, Beijing 100871, China; and.
Chuan
C
He
Beijing National Laboratory for Molecular Sciences,Biodynamic Optical Imaging Center,Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and gaoyq@pku.edu.cn zhaoxs@pku.edu.cn.
Yi Qin
YQ
Gao
Beijing National Laboratory for Molecular Sciences,State Key Laboratory for Structural Chemistry of Unstable and Stable Species,Biodynamic Optical Imaging Center,Department of Chemical Biology and gaoyq@pku.edu.cn zhaoxs@pku.edu.cn.
Xin Sheng
XS
Zhao
D020137:Base Pair Mismatch / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics*; D055592:Biophysical Phenomena / Q000235:genetics*; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D059371:DNA, B-Form / Q000737:chemistry* / Q000235:genetics; D005453:Fluorescence; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D010777:Photochemistry / Q000379:methods; D013816:Thermodynamics
D059371:DNA, B-Form; D004247:DNA
fluctuation spectroscopy; free-energy landscape; integrated tempering sampling; rate constants