title: Metadynamics simulation study on the conformational transformation of HhaI methyltransferase: an induced-fit base-flipping hypothesis.
abstract: DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify the genetic information hidden in DNA. To investigate the conversion process of base flipping in the HhaI methyltransferase (M.HhaI), we performed different molecular simulation approaches on M.HhaI-DNA-S-adenosylhomocysteine ternary complex. The results demonstrate that the nonspecific binding of DNA to M.HhaI is initially induced by electrostatic interactions. Differences in chemical environment between the major and minor grooves determine the orientation of DNA. Gln237 at the target recognition loop recognizes the GCGC base pair from the major groove side by hydrogen bonds. In addition, catalytic loop motion is a key factor during this process. Our study indicates that base flipping is likely to be an "induced-fit" process. This study provides a solid foundation for future studies on the discovery and development of mechanism-based DNA methyltransferases regulators.
authors.affiliation: College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China ; Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, China.
authors.forename: Lu
authors.identifier: 0000-0003-2724-5406
authors.initials: L
authors.lastname: Jin
authors.affiliation: College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Kongkai
authors.identifier: 0000-0003-2293-3568
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mingyue
authors.identifier: 0000-0002-3323-3092
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, China.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D002384:Catalysis; D020134:Catalytic Domain; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015257:DNA-Cytosine Methylases / Q000737:chemistry / Q000235:genetics*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D012435:S-Adenosylhomocysteine / Q000378:metabolism
chemical_list: D004247:DNA; D012435:S-Adenosylhomocysteine; C037664:DNA modification methylase HhaI; D015257:DNA-Cytosine Methylases