Methylation-targeted specificity of the DNA binding proteins R.DpnI and MeCP2 studied by molecular dynamics simulations.
Siba ShanakOzlem UlucanVolkhard HelmsPublished in: Journal of molecular modeling (2017)
DNA methylation plays a major role in organismal development and the regulation of gene expression. Methylation of cytosine bases and the cellular roles of methylated cytosine in eukaryotes are well established, as well as methylation of adenine bases in bacterial genomes. Still lacking, however, is a general mechanistic understanding, in structural and thermodynamic terms, of how proteins recognize methylated DNA. Toward this aim, we present the results of molecular dynamics simulations, alchemical free energy perturbation, and MM-PBSA calculations to explain the specificity of the R.DpnI enzyme from Streptococcus pneumonia in binding to adenine-methylated DNA with both its catalytic and winged-helix domains. We found that adenine-methylated DNA binds more favorably to the catalytic subunit of R.DpnI (-4 kcal mol-1) and to the winged-helix domain (-1.6 kcal mol-1) than non-methylated DNA. In particular, N6-adenine methylation is found to enthalpically stabilize binding to R.DpnI. In contrast, C5-cytosine methylation entropically favors complexation by the MBD domain of the human MeCP2 protein with almost no contribution of the binding enthalpy.
Keyphrases
- molecular dynamics simulations
- dna methylation
- dna binding
- genome wide
- circulating tumor
- gene expression
- cell free
- single molecule
- molecular docking
- transcription factor
- endothelial cells
- nucleic acid
- circulating tumor cells
- magnetic resonance
- amino acid
- cancer therapy
- molecular dynamics
- induced pluripotent stem cells
- small molecule
- pluripotent stem cells
- biofilm formation
- staphylococcus aureus
- drug delivery