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Biophys J, January 2001, p. 455-468, Vol. 80, No. 1

Molecular Dynamics of DNA Quadruplex Molecules Containing Inosine, 6-Thioguanine and 6-Thiopurine

Richard Stefl,*dagger Nad'a Spacková,Dagger §|| Imre Berger,** Jaroslav Koca,* and Ji&rbreve;í SponerDagger §

 *Laboratory of Biomolecular Structure and Dynamics,  dagger Department of Theoretical and Physical Chemistry, and  ||Department of Physical Electronics, Faculty of Science, Masaryk University, 611 37 Brno, Czech Republic;  Dagger Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic;  §J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, 182 23 Prague, Czech Republic; and  **Institute for Molecular Biology and Biophysics, CH-8093 Zürich, Switzerland

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.

Biophys J, January 2001, p. 455-468, Vol. 80, No. 1
© 2001 by the Biophysical Society   0006-3495/01/01/455/14  $2.00


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