The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch

Abstract

The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with S-substitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening.

Fig 1. (a) Chemical structures and labelling of guanine and 6-thioguanine, (b) the conversion of cytosine to thymine.

Fig 2. Parameters describing duplex structure [16].

Fig 3. Structures of (a) paired G:C (b) paired G:T with wobble base pair structure and (c) paired G:T with bifurcated structure.

Fig 4. Variation of distances between potentially hydrogen-bonded atoms with time for the G:C duplex.

Black line O6-N4 distance, grey line N1-N3 distance, dotted line N2-O2 distance.

Fig 5. Variation of distances between potentially hydrogen-bonded atoms with time for the G:T duplex.

Black line O6-N3 distance, grey line N2-O2 distance, dashed line N1-O2 distance.

Fig 6. Variation of the width of the major groove with time for the four duplexes studied.

Continuous black line G:C duplex, dotted line G:T duplex, continuous grey line G^S:C duplex and dashed line G^S:T duplex.

Fig 7. Variation of distances between potentially hydrogen-bonded atoms with time for the G^S:C duplex.

Black line S6-N4 distance, grey line N1-N3 distance, dotted line N2-O2 distance.

Fig 8. Comparison of opening for S-substituted and non-substituted duplexes.

Fig 9. Variation of distances between potentially hydrogen-bonded atoms with time for the G^S:T duplex.

Black line S6-N3 distance, grey line N2-O2 distance, dotted line N1–O2 distance.