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Effects of nucleotide bromination on the stabilities of Z‐RNA and Z‐DNA: A molecular mechanics/thermodynamic perturbation study
Author(s) -
Ross Wilson S.,
Hardin Charles C.,
Tinoco, Ignacio,
Rao Shashidhar N.,
Pearlman David A.,
Kollman Peter A.
Publication year - 1989
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360281111
Subject(s) - chemistry , guanosine , molecular mechanics , dna , oligonucleotide , rna , molecule , halogenation , nucleotide , crystallography , stereochemistry , molecular dynamics , computational chemistry , organic chemistry , biochemistry , gene
The structures of Z I ‐ and Z II ‐ 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 H 2 O 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 br 5 C 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 Z II ‐ form oligonucleotides are lower than those of the corresponding Z I ‐ form molecules for both RNA and DNA. Previous x‐ray diffraction, nmr, and molecular mechanics studies indicate that hydration effects may favor the Z I ‐ conformation over the Z II ‐ form in DNA. Molecular mechanics calculations show that the Z II –Z I 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 Z II 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 Z II ‐ form molecule. Both of these interactions are less likely in the Z I ‐ form molecule: the former due to the orientation of the GpC phosphate away from the guanosine ribose in the Z I form, and the latter apparently due to competitive hydrogen bonding of the cytidine 2′‐hydroxyl hydrogen with the cytosine carbonyl oxygen in the Z I 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.