ArticleBiochemistry2013
DNA cytosine methylation: structural and thermodynamic characterization of the epigenetic marking mechanism.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 43 citations in OpenAlex.
- Cytosine analogues as DNA methyltransferase substrates.Nucleic acids research · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Base Dynamics in theThe journal of physical chemistry. B · 2023Article
- Insights into the Inhibitory Mechanisms of the Covalent Drugs for DNMT3A.International journal of molecular sciences · 2023Article
- Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas.Clinical epigenetics · 2023Article
- Unveiling the methyl transfer mechanisms in the epigenetic machinery DNMT3A-3 L: A comprehensive study integrating assembly dynamics with catalytic reactions.Computational and structural biotechnology journal · 2023Article
- Genome-wide identification and transcriptional characterization of DNA methyltransferases conferring temperature-sensitive male sterility in wheat.BMC genomics · 2021Article
- Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B.Nucleic acids research · 2020Article
- Understanding the R882H mutation effects of DNA methyltransferase DNMT3A: a combination of molecular dynamics simulations and QM/MM calculations.RSC advances · 2019Article
- Children's DAT1 Polymorphism Moderates the Relationship Between Parents' Psychological Profiles, Children's DAT Methylation, and Their Emotional/Behavioral Functioning in a Normative Sample.International journal of environmental research and public health · 2019Article
- How a single 5-methylation of cytosine regulates the recognition of C/EBPβ transcription factor: a molecular dynamic simulation study.Journal of molecular modeling · 2018Article
- Can 5-methylcytosine analogues with extended alkyl side chains guide DNA methylation?Chemical communications (Cambridge, England) · 2018Article
- In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1.PloS one · 2017Article
- Abnormal Hypermethylation of the VDAC2 Promoter is a Potential Cause of Idiopathic Asthenospermia in Men.Scientific reports · 2016Article
- Human DNMT1 transition state structure.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.Journal of computational chemistry · 2015Article
- 5-Methylation of cytosine in CG:CG base-pair steps: a physicochemical mechanism for the epigenetic control of DNA nanomechanics.The journal of physical chemistry. B · 2013Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
DNA cytosine methyltransferases regulate the expression of the genome through the precise epigenetic marking of certain cytosines with a methyl group, and aberrant methylation is a hallmark of human diseases including cancer. Targeting these enzymes for drug design is currently a high priority. We have utilized ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations to investigate extensively the reaction mechanism of the representative DNA methyltransferase HhaI (M.HhaI) from prokaryotes, whose overall mechanism is shared with the mammalian enzymes. We obtain for the first time full free energy profiles for the complete reaction, together with reaction dynamics in atomistic detail. Our results show an energetically preferred mechanism in which nucleophilic attack of cytosine C5 on the S-adenosyl-L-methionine (AdoMet) methyl group is concerted with formation of the Michael adduct between a conserved Cys in the active site with cytosine C6. Spontaneous and reversible proton transfer between a conserved Glu in the active site and cytosine N3 at the transition state was observed in our simulations, revealing the chemical participation of this Glu residue in the catalytic mechanism. Subsequently, the β-elimination of the C5 proton utilizes as base an OH(-) derived from a conserved crystal water that is part of a proton wire water channel, and this syn β-elimination reaction is the rate-limiting step. Design of novel cytosine methylation inhibitors would be advanced by our structural and thermodynamic characterization of the reaction mechanism.
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Registered trials
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