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Kotulic Bunta, J.*; Laaksonen, A.*; Pinak, M.; Nemoto, Toshiyuki*
Computational Biology and Chemistry, 30(2), p.112 - 119, 2006/04
Times Cited Count：3 Percentile：21.78(Biology)Due to their lethal consequences, single and double strand breaks are among the most important and dangerous DNA lesions. This work defines and analyzes a DNA with single strand break as a template study for future complex analyses of biologically serious double strand break damage and its enzymatic repair mechanisms. Besides a non-damaged DNA serving as a reference system, system with open valences of the atoms at the strand break ends as well as a system with filled valences was simulated. As for the results, the system with open valences is partly disrupted, and the system with filled valences is stabilized by forming new hydrogen bonds between two strand endings.
Schyman, P.*; Danielsson, J.*; Pinak, M.; Laaksonen, A.*
Journal of Physical Chemistry A, 109(8), p.1713 - 1719, 2005/02
Times Cited Count：39 Percentile：77.38(Chemistry, Physical)We have examined the role of the catalytic lysine (Lys 249) in breaking the glycosidic bond of 8-oxoguanine in the enzyme human 8-oxoguanine DNA glycosylase. It has been assumed that this lysine acts as a nucleophile in a S
2 type of reaction after being activated through a donation of a proton to a strictly conserved aspartate. We use hybrid density functional theory to characterize both associative and dissociative pathways. We find that the smallest energetical barrier involves a S1 type of mechanism where the lysine electrostatically stabilizes the dissociating base and then donates a proton with a very small barrier and then finally attacks the sugar ring to create the covalently bounded protein-DNA intermediate complex. Reported findings give further support to the assumption that a dissociative mechanism may be the preferred mode of action for this type of enzymes.
Pinak, M.; Laaksonen, A.
Molecular Mechanisms for Radiation-Induced Cellular Response and Cancer Development, p.266 - 273, 2003/00
The molecular dynamics (MD) simulations of DNA mutagenic oxidative lesion - 7,8-dihydro-8-oxoguanine (8-oxoG), single and complexed with the repair enzyme - human oxoguanine glycosylase 1 (hOGG1), were performed for 1 nanosecond (ns) in order to determine structural changes at the DNA molecule and to describe a dynamical process of DNA-enzyme complex formation. The broken hydrogen bonds resulting in locally collapsed B-DNA structure were observed at the lesion site. In addition the adenine on the complementary strand (separated from 8-oxoG by 1 base pair) was flipped-out of the DNA double helix. In the case of simulation of DNA and repair enzyme hOGG1, the DNA-enzyme complex was formed after 500 picoseconds of MD that lasted stable until the simulation was terminated at 1 ns.
