Most cited article - PubMed ID 10496422
Interactions of hydrated IIa and IIb group metal cations with thioguanine-cytosine DNA base pair: Ab initio and density functional theory investigation of polarization effects, differences among cations, and flexibility of the cation hydration shell
The ability of the four-stranded guanine (G)-DNA motif to incorporate nonstandard guanine analogue bases 6-oxopurine (inosine, I), 6-thioguanine (tG), and 6-thiopurine (tI) has been investigated using large-scale molecular dynamics simulations. The simulations suggest that a G-DNA stem can incorporate inosines without any marked effect on its structure and dynamics. The all-inosine quadruplex stem d(IIII)(4) shows identical dynamical properties as d(GGGG)(4) on the nanosecond time scale, with both molecular assemblies being stabilized by monovalent cations residing in the channel of the stem. However, simulations carried out in the absence of these cations show dramatic differences in the behavior of d(GGGG)(4) and d(IIII)(4). Whereas vacant d(GGGG)(4) shows large fluctuations but does not disintegrate, vacant d(IIII)(4) is completely disrupted within the first nanosecond. This is a consequence of the lack of the H-bonds involving the N2 amino group that is not present in inosine. This indicates that formation of the inosine quadruplex could involve entirely different intermediate structures than formation of the guanosine quadruplex, and early association of cations in this process appears to be inevitable. In the simulations, the incorporation of 6-thioguanine and 6-thiopurine sharply destabilizes four-stranded G-DNA structures, in close agreement with experimental data. The main reason is the size of the thiogroup leading to considerable steric conflicts and expelling the cations out of the channel of the quadruplex stem. The G-DNA stem can accommodate a single thioguanine base with minor perturbations. Incorporation of a thioguanine quartet layer is associated with a large destabilization of the G-DNA stem whereas the all-thioguanine quadruplex immediately collapses.
- MeSH
- Biophysics MeSH
- Biophysical Phenomena MeSH
- DNA chemistry MeSH
- Inosine chemistry MeSH
- Ion Channels chemistry MeSH
- Nucleic Acid Conformation * MeSH
- Mercaptopurine chemistry MeSH
- Models, Molecular MeSH
- Sodium chemistry MeSH
- Thermodynamics MeSH
- Thioguanine chemistry MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA MeSH
- Inosine MeSH
- Ion Channels MeSH
- Mercaptopurine MeSH
- Sodium MeSH
- Thioguanine MeSH
