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Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs.

Koller AN, Bozilovic J, Engels JW, Gohlke H - Nucleic Acids Res. (2010)

Bottom Line: Decomposing the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs.Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol(-1) compared to non-fluorinated analogs.Z is found to be the least destabilizing universal base in the context of RNA known to date.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

ABSTRACT
The thermodynamics of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estimated by potential of mean force calculations. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol(-1). Decomposing the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol(-1) compared to non-fluorinated analogs. This is attributed to stabilizing C-F(...)H-N dipolar interactions and stronger N(...)H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first experimental evidence for nitrogen-containing heterocylces as bioisosteres of aromatic rings bearing fluorine atoms.

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Free-energy profiles as a function of the separation distance for the base pairs AP (blue), CP (red), AZ (green) and CZ (magenta).
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Figure 6: Free-energy profiles as a function of the separation distance for the base pairs AP (blue), CP (red), AZ (green) and CZ (magenta).

Mentions: Following this idea, and using E as a template, known to date as the least destabilizing universal base in the context of duplex RNA, we investigated the N-heterocyclic analog 7-methyl-7H-purine (P) with respect to its base pairing properties. To the best of our knowledge, a 7-N-linked purine has not yet been applied as a base analog, in contrast to a 9-N-linked purine (56,66). The free-energy curves of pairing between AP and CP are shown in Figure 6, together with curves of the 9-deaza analog of P, 5-methyl-5H-pyrrolo[3,2-d]pyrimidine (Z), paired to A and C, respectively. Z is a more stable analog of P (see below). Not surprisingly, the PMFs are very similar for P and Z, because P and Z differ only in the structure of the five-membered ring, which is not directly involved in interactions with the natural base. Free energies of pairing are given in Table 1. The difference in the free energy of P(Z) pairing with either A or C is −0.29 kcal mol−1 (−0.21 kcal mol−1). This difference is similar to the one obtained for B (E) pairing to A or C, suggesting that P and Z will act as universal bases as well. Furthermore, the pairing free energies involving P or Z are comparable to those obtained for B (E), but more favorable by at least 0.43 kcal mol−1 than the pairing free energy of M. This points to the existence of dipolar interactions between P (Z) and the natural bases and demonstrates that heterocyclic nitrogen indeed can act as a mimic for an aromatic C–F group in these cases. These results led us to suggest using P and Z as novel universal bases in the context of duplex RNA.Figure 6.


Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs.

Koller AN, Bozilovic J, Engels JW, Gohlke H - Nucleic Acids Res. (2010)

Free-energy profiles as a function of the separation distance for the base pairs AP (blue), CP (red), AZ (green) and CZ (magenta).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875010&req=5

Figure 6: Free-energy profiles as a function of the separation distance for the base pairs AP (blue), CP (red), AZ (green) and CZ (magenta).
Mentions: Following this idea, and using E as a template, known to date as the least destabilizing universal base in the context of duplex RNA, we investigated the N-heterocyclic analog 7-methyl-7H-purine (P) with respect to its base pairing properties. To the best of our knowledge, a 7-N-linked purine has not yet been applied as a base analog, in contrast to a 9-N-linked purine (56,66). The free-energy curves of pairing between AP and CP are shown in Figure 6, together with curves of the 9-deaza analog of P, 5-methyl-5H-pyrrolo[3,2-d]pyrimidine (Z), paired to A and C, respectively. Z is a more stable analog of P (see below). Not surprisingly, the PMFs are very similar for P and Z, because P and Z differ only in the structure of the five-membered ring, which is not directly involved in interactions with the natural base. Free energies of pairing are given in Table 1. The difference in the free energy of P(Z) pairing with either A or C is −0.29 kcal mol−1 (−0.21 kcal mol−1). This difference is similar to the one obtained for B (E) pairing to A or C, suggesting that P and Z will act as universal bases as well. Furthermore, the pairing free energies involving P or Z are comparable to those obtained for B (E), but more favorable by at least 0.43 kcal mol−1 than the pairing free energy of M. This points to the existence of dipolar interactions between P (Z) and the natural bases and demonstrates that heterocyclic nitrogen indeed can act as a mimic for an aromatic C–F group in these cases. These results led us to suggest using P and Z as novel universal bases in the context of duplex RNA.Figure 6.

Bottom Line: Decomposing the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs.Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol(-1) compared to non-fluorinated analogs.Z is found to be the least destabilizing universal base in the context of RNA known to date.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

ABSTRACT
The thermodynamics of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estimated by potential of mean force calculations. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol(-1). Decomposing the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol(-1) compared to non-fluorinated analogs. This is attributed to stabilizing C-F(...)H-N dipolar interactions and stronger N(...)H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first experimental evidence for nitrogen-containing heterocylces as bioisosteres of aromatic rings bearing fluorine atoms.

Show MeSH
Related in: MedlinePlus