Effect O6-guanine alkylation on DNA flexibility studied by comparative molecular dynamics simulations

Mahmut Kara, Tomas Drsata, Filip Lankas, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Alkylation of guanine at the O6 atom is a highly mutagenic DNA lesion because it alters the coding specificity of the base causing G:C to A:T transversion mutations. Specific DNA repair enzymes, e.g. O6-alkylguanin-DNA-Transferases (AGT), recognize and repair such damage after looping out the damaged base to transfer it into the enzyme active site. The exact mechanism how the repair enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. The O6-alkylation of guanine may change the deformability of DNA which may facilitate the initial binding of a repair enzyme at the damaged site. In order to characterize the effect of O6-methyl-guanine (O6-MeG) containing base pairs on the DNA deformability extensive comparative molecular dynamics (MD) simulations on duplex DNA with central G:C, O6-MeG:C or O6-MeG:T base pairs were performed. The simulations indicate significant differences in the helical deformability due to the presence of O6-MeG compared to regular undamaged DNA. This includes enhanced base pair opening, shear and stagger motions and alterations in the backbone fine structure caused in part by transient rupture of the base pairing at the damaged site and transient insertion of water molecules. It is likely that the increased opening motions of O6-MeG:C or O6-MeG:T base pairs play a decisive role for the induced fit recognition or for the looping out of the damaged base by repair enzymes.

Original languageEnglish
Pages (from-to)23-32
Number of pages10
Issue number1
StatePublished - 1 Jan 2015
Externally publishedYes


  • DNA alkylation
  • DNA damage
  • DNA repair
  • molecular dynamics simulation
  • molecular simulation


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