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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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Top (left panel) and side view (right panel) of the water density in the umbrella sampling simulation at the water-separated minimum for base pairs (a) AU, (b) AB, (c) AM, respectively. Cyan solid regions represent a 2.5-fold higher and magenta mesh regions a 2.0-fold higher water density than the bulk density of 0.99 g cm−3.
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Figure 3: Top (left panel) and side view (right panel) of the water density in the umbrella sampling simulation at the water-separated minimum for base pairs (a) AU, (b) AB, (c) AM, respectively. Cyan solid regions represent a 2.5-fold higher and magenta mesh regions a 2.0-fold higher water density than the bulk density of 0.99 g cm−3.

Mentions: In contrast, for AB, base pairing is enthalpically disfavored by ∼4 kcal mol−1. Apparently, the loss of the base–water interaction energy is not overcompensated by the formation of base–base interactions, as demonstrated by a very similar enthalpic component at the location of the barrier and the contact minimum. Schweitzer et al. (1) already proposed a net energetic repulsion between A and B and suggested the cost of removing waters of solvation bound to A as a reason (54,55). In fact, computed water densities for AU and AB configurations at the water-separated minima show two solvating waters between the bases, which are expelled upon formation of the contact pair (Figure 3). In contrast to the AU case, little energetic compensation for breaking these hydrogen bonds is available in the AB case due to B’s inability to form measurable hydrogen bonds with A (3,56). This is corroborated by quantum chemical studies, which predict a significantly lower stability for the pairing of fluorinated base analogs and A compared to a Watson–Crick pair (29,57,58).Figure 3.


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)

Top (left panel) and side view (right panel) of the water density in the umbrella sampling simulation at the water-separated minimum for base pairs (a) AU, (b) AB, (c) AM, respectively. Cyan solid regions represent a 2.5-fold higher and magenta mesh regions a 2.0-fold higher water density than the bulk density of 0.99 g cm−3.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: Top (left panel) and side view (right panel) of the water density in the umbrella sampling simulation at the water-separated minimum for base pairs (a) AU, (b) AB, (c) AM, respectively. Cyan solid regions represent a 2.5-fold higher and magenta mesh regions a 2.0-fold higher water density than the bulk density of 0.99 g cm−3.
Mentions: In contrast, for AB, base pairing is enthalpically disfavored by ∼4 kcal mol−1. Apparently, the loss of the base–water interaction energy is not overcompensated by the formation of base–base interactions, as demonstrated by a very similar enthalpic component at the location of the barrier and the contact minimum. Schweitzer et al. (1) already proposed a net energetic repulsion between A and B and suggested the cost of removing waters of solvation bound to A as a reason (54,55). In fact, computed water densities for AU and AB configurations at the water-separated minima show two solvating waters between the bases, which are expelled upon formation of the contact pair (Figure 3). In contrast to the AU case, little energetic compensation for breaking these hydrogen bonds is available in the AB case due to B’s inability to form measurable hydrogen bonds with A (3,56). This is corroborated by quantum chemical studies, which predict a significantly lower stability for the pairing of fluorinated base analogs and A compared to a Watson–Crick pair (29,57,58).Figure 3.

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