63. Molecular Dynamics Simulation of a DNA Containing a Single Strand Break
Hiroshi Yamaguchi, Joerg-Gerald Siebers1, Akira Furukawa, Nobumasa Otagiri2 and Roman Osman3 (1 RIKEN; 2 Univ. of Tokyo; 3 Mount Sinai School of Medicine)
Keywords: DNA damage, single strand break (ssb, SSB), molecular dynamics, computer simulation, essential dynamics
Molecular dynamics (MD) simulations were performed for a dodecamer DNA containing a single strand break (SSB), which the authors assumed to be the simplest type of SSB: it had two ends, 3'-OH deoxyribose and 5'-OH phosphate. Molecular force field parameters of the 5'-OH phosphate region were newly evaluated using the ab initio program package GAMESS at the HF/6-31G level, while the force field of the 3'-OH end of deoxyribose has been well defined within the database.
To study possible sequence dependence of SSB, four dodecamers of the same sequence containing a SSB in a different position, (1) G8-C9, (2) G16-C17, (3) A18-A19 and (4) T6-T7, were considered. TIP3 water and counter ions (Na+) in a box were added and minimization and heating up to 300 K and production run up to a time of 1ns were carried out by AMBER 4.1.
Root Mean Square Distances (RMSDs, not shown here) showed that all cases were stabilized after 200 ps. This work is the first successful MD calculation for DNA containing a SSB. As seen in snapshots of conformations of DNA at the time of 1 ns (Fig.20), conformational changes were surprisingly small.
A detailed analysis, by the program Dials and Windows, of the equilibrated average structure supported this findings. Among inter-base pair parameters, Rise, Twist may adjust local conformation at the site of a SSB such that the SSB does not drive the DNA structure into overall corruption. This finding may be supported by the calculations of stacking force between base pairs by Sarai et al.. Their calculations suggested that only the stacking force between base pairs could form the double helix DNA structure, that is, no so much change would be expected for the present type of SSB.
However, dynamical properties calculated using the essential dynamics, where the program WHATIF was applied, showed some noticeable difference between DNA containing a SSB and normal DNA, and among DNAs that had a SSB in a different position. This difference may be a signal for recognition of this type of break by a repair enzyme. Study along this working hypothesis is in progress by the authors.
As mentioned in various reports, SSB produced by ionizing radiations may well be far more complex than presently thought, and non-specific in position as well as in chemical forms. However, if molecular structure of the SSB can be specified, the authors believe that this approach may work for radiation induced SSB and disclose molecular behavior of the SSB, and hence provide useful insight about possible mechanisms of the repair process by repair enzymes.
Yamaguchi, H. et al.: Radiat. Prot. Dosim. in press.
|Fig.20.||Snapshots of normal and SSB-containing DNA structures taken at simulation time lns. The positions of SSB sites are indicated by arrows.|
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