Mechanism studies of the activation of DNA methyltransferase DNMT1 triggered by histone H3 ubiquitination,revealed by multi-scale molecular dynamics simulations

作     者：Jixue Sun Fei Liu Longxiao Yuan Ning-Ning Pang Bing Zhu Na Yang 

作者机构：State Key Laboratory of Medicinal Chemical BiologyCollege of Pharmacy and Key Laboratory of Medical Data Analysis and Statistical Research of TianjinNankai UniversityTianjin 300353China National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China 

出 版 物：《Science China(Life Sciences)》 (中国科学（生命科学英文版）)

年 卷 期：2023年第66卷第2期

页      面：313-323页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071007[理学-遗传学] 

基　　金：supported by the Chinese Ministry of Science and Technology and National Natural Science Foundation of China(2019YFA0508902,2018YFA0107004,32170549,31870737,22103040) the National Laboratory of Biomacromolecules(2021kf05) the Fundamental Research Funds for the Central Universities and Tianjin Funds for Distinguished Young Scientists(17JCJQJC45900)。 

主　　题：DNA methyltransferase conformational change molecular dynamics simulation activation molecular mechanism 

摘      要：DNMT1 is a DNA methyltransferase that catalyzes and maintains methylation in CpG dinucleotides.It blocks the entrance of DNA into the catalytic pocket via the replication foci targeting sequence(RFTS)domain.Recent studies have shown that an H3-tail-conjugated two-mono-ubiquitin mark(H3Ub2)activates DNMT1 by binding to the RFTS domain.However,the activation mechanism of DNMT1 remains unclear.In this work,we combine various sampling methods of extensive simulations,including conventional molecular dynamics,Gaussian-accelerated molecular dynamics,and coarse-grained molecular dynamics,to elucidate the activation mechanism of DNMT1.Geometric and energy analyses show that binding of H3Ub2 to the RFTS domain of DNMT1 results in the bending of theα4-helix in the RFTS domain at approximately 30°–35°,and the RFTS domain rotates~20°anti-clockwise and moves~3?away from the target recognition domain(TRD).The hydrogen-bonding network at the RFTSTRD interface is significantly disrupted,implying that the RFTS domain is dissociated from the catalytic core,which contributes to activating the auto-inhibited conformation of DNMT1.These results provide structural and dynamic evidence for the role of H3Ub2 in regulating the catalytic activity of DNMT1.