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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.10 P.883-895


Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter

Author(s):  Jinru WENG, Shuo YANG, Jinkang SHEN, Hongsen LIU, Yuzi XU, Dongyun HAO, Shan WANG

Affiliation(s):  Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China; more

Corresponding email(s):   shan_wang@zju.edu.cn, dyhao@cjaas.com

Key Words:  c-Myb, DNA-specific recognition mechanism, Molecular dynamics simulation, DNA major groove width, Electrostatic potential

Jinru WENG, Shuo YANG, Jinkang SHEN, Hongsen LIU, Yuzi XU, Dongyun HAO, Shan WANG. Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter[J]. Journal of Zhejiang University Science B, 2023, 24(10): 883-895.

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author="Jinru WENG, Shuo YANG, Jinkang SHEN, Hongsen LIU, Yuzi XU, Dongyun HAO, Shan WANG",
journal="Journal of Zhejiang University Science B",
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%T Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter
%A Jinru WENG
%A Shuo YANG
%A Jinkang SHEN
%A Hongsen LIU
%A Yuzi XU
%A Dongyun HAO
%A Shan WANG
%J Journal of Zhejiang University SCIENCE B
%V 24
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%P 883-895
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200634

T1 - Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter
A1 - Jinru WENG
A1 - Shuo YANG
A1 - Jinkang SHEN
A1 - Hongsen LIU
A1 - Yuzi XU
A1 - Dongyun HAO
A1 - Shan WANG
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 10
SP - 883
EP - 895
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200634

This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation. Therefore, we chose the chicken myeloid gene, mitochondrial import protein 1 (mim-1), as a target to study the binding specificity between potential dual-Myb-binding sites. The c-Myb-binding site in mim-1 is a pseudo-palindromic sequence AACGGTT, which contains two AACNG consensuses. Simulation studies in different biological scenarios revealed that c-Myb binding with mim-1 in the forward strand (complex F) is more stable than that in the reverse strand (complex R). The principal component analysis (PCA) dynamics trajectory analyses suggested an opening motion of the recognition helices of R2 and R3 (R2R3), resulting in the dissociation of DNA from c-Myb in complex R at 330 K, triggered by the reduced electrostatic potential on the surface of R2R3. Furthermore, the DNA confirmation and hydrogen-bond interaction analyses indicated that the major groove width of DNA increased in complex R, which affected on the hydrogen-bond formation ability between R2R3 and DNA, and directly resulted in the dissociation of DNA from R2R3. The steered molecular dynamics (SMD) simulation studies also suggested that the electrostatic potential, major groove width, and hydrogen bonds made major contribution to the DNA‍-specific recognition. In vitro trials confirmed the simulation results that c-Myb specifically bound to mim-1 in the forward strand. This study indicates that the three-dimensional (3D) structure features play an important role in the DNA-specific recognition mechanism by c-Myb besides the AACNG consensuses, which is beneficial to understanding the cell early differentiation and proliferation regulated by c-Myb, as well as the prediction of novel c-Myb-binding motifs in tumorigenesis.


摘要:本研究旨在探索c-Myb转录因子在调控细胞早期分化和增殖过程中的DNA特异性识别机制。我们以鸡髓系基因mim-1为研究对象,研究其潜在双c-Myb结合位点的结合特异性。mim-1的c-Myb结合位点是一个伪回文序列AACGGTT,正反方向分别包含1个c-Myb结合保守序列AACNG。不同条件下的重复分子动力学模拟研究表明,c-Myb与mim-1正链的结合(复合物F)比与反链的结合(复合物R)更稳定。主成分分析(PCA)动力学轨迹分析表明,在330 K温度下,c-Myb识别螺旋R2和R3(R2R3)的开放运动导致复合物R中DNA与c-Myb解离,且此开放运动是由R2R3表面静电势降低引起。同时,DNA构象和氢键相互作用分析表明,复合物R中DNA的大沟宽度增加影响了R2R3与DNA间的氢键形成,直接导致DNA与R2R3的解离。拉伸分子动力学模拟研究进一步表明,静电势、DNA大沟宽度和氢键对DNA特异性识别起到重要作用。体外实验证实了计算模拟结果,即c-Myb只与mim-1正链结合。本研究表明,除一维保守序列AACNG外,三维结构特性对c-Myb的DNA特异性识别也起着重要作用。本研究结果有助于理解c-Myb在细胞早期分化和增殖中的调控机制,以及预测开发由c-Myb结合位点增多引起的肿瘤发生标志物。


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