Effects of nucleotide bromination on the stabilities of Z‐RNA and Z‐DNA: A molecular mechanics/thermodynamic perturbation study

Abstract

The structures of ZI- and ZII-form RNA and DNA oligonucleotides were energy minimized in vacuum using the AMBER molecular mechanics force field. Alternating C-G sequences were studied containing either unmodified nucleotides, 8-bromoguanosine in place of all guanosine residues, 5-bromocytidine in place of all cytidine residues, or all modified residues. Some molecules were also energy minimized in the presence of H2O and cations. Free energy perturbation calculations were done in which G8 and C5 hydrogen atoms in one or two residues of Z-form RNAs and DNAs were replaced in a stepwise manner by bromines. Bromination had little effect on the structures of the energy-minimized molecules. Both the minimized molecular energies and the results of the perturbation calculations indicate that bromination of guanosine at C8 will stabilize the Z forms of RNA and DNA relative to the nonbrominated Z form, while bromination of cytidine at C5 stabilizes Z-DNA and destabilizes Z-RNA. These results are in agreement with experimental data. The destabilizing effect of br5C in Z-RNAs is apparently due to an unfavorable interaction between the negatively charged C5 bromine atom and the guanosine hydroxyl group. The vacuum-minimized energies of the ZII-form oligonucleotides are lower than those of the corresponding ZI-form molecules for both RNA and DNA. Previous x-ray diffraction, nmr, and molecular mechanics studies indicate that hydration effects may favor the ZI conformation over the ZII form in DNA. Molecular mechanics calculations show that the ZII-ZI energy differences for the RNAs are greater than three times those obtained for the DNAs. This is due to structurally reinforcing hydrogen-bonding interactions involving the hydroxyl groups in the ZII form, especially between the guanosine hydroxyl hydrogen atom and the 3'-adjacent phosphate oxygen. In addition, the cytidine hydroxyl oxygen forms a hydrogen bond with the 5'-adjacent guanosine amino group in the ZII-form molecule. Both of these interactions are less likely in the ZI-form molecule: the former due to the orientation of the GpC phosphate away from the guanosine ribose in the ZI form, and the latter apparently due to competitive hydrogen bonding of the cytidine 2'-hydroxyl hydrogen with the cytosine carbonyl oxygen in the ZI form. The hydrogen-bonding interaction between the cytidine hydroxyl oxygen and the 5'-adjacent guanosine amino group in Z-RNA twists the amino group out of the plane of the base. This may be responsible for differences in the CD and Raman spectra of Z-RNA and Z-DNA.

Copper‐Catalyzed Mild Nitration of Protected Anilines

“…However, these bands almost disappear from the SERS of ds br C5. It has been shown that the C5‐bromination has little effect on the atomic charge distribution of cytosine19 as well as on the overall duplex stability 19–20. Thus, we deduce that in the duplex conformation the NH 2 group geometry is largely determined by the strong Watson–Crick base pairing which significantly reduces the influence of the Br group on the amino conformation (see Supporting Information, Figure S10, for a more detailed discussion).…”

The free energy difference between simple models of B- and Z-DNA: Computer simulation and theoretical predictions

“…The FEP approach has been employed by Kollman's group in the estimation of the change in ⌬G B→Z caused by certain modifications of the DNA sequence. [36][37][38] However, the actual free energy change of the B-to Z-DNA transition cannot be computed by this method due to the dissimilarity of the conformers which results in insurmountable sampling problems. Even with an extremely simplified DNA model, a direct estimation of ⌬G B→Z through the FEP method would require the simulation of a huge number of intermediate models, which is exceedingly expensive in terms of computer time.…”

Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides

“…The shifts in equilibrium between B and Z conformations occur due to the steric hindrance of bromo-substitution at the C8 position. Moreover, the substitution of the bromo group interacts with the phosphate backbone of the DNA to form a syn conformation [93][94][95].…”