Limits...
Stability and kinetics of G-quadruplex structures.

Lane AN, Chaires JB, Gray RD, Trent JO - Nucleic Acids Res. (2008)

Bottom Line: Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes.Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium.The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology Program, JG Brown Cancer Center, University of Louisville, KY 40202, USA. anlane01@gwise.louisville.edu

ABSTRACT
In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

Show MeSH
Stacked quartets with coordinated monovalent ion. (A) Parallel stacked quartets with Na+ stabilization (purple spheres) from (d(TGGGGT)4), (B) parallel stacked quartets with K+ stabilization (green spheres) from (dA(GGGTTA)3GGG), (C) d(TGGGGT)4 stacking in space filling representation, (D) dA(GGGTTA)3GGG stacking in space filling representation. Loops have been removed from C and D for clarity.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2553573&req=5

Figure 2: Stacked quartets with coordinated monovalent ion. (A) Parallel stacked quartets with Na+ stabilization (purple spheres) from (d(TGGGGT)4), (B) parallel stacked quartets with K+ stabilization (green spheres) from (dA(GGGTTA)3GGG), (C) d(TGGGGT)4 stacking in space filling representation, (D) dA(GGGTTA)3GGG stacking in space filling representation. Loops have been removed from C and D for clarity.

Mentions: G-quartets are based on the formation of a (nearly) square planar array of four guanine bases, as shown in Figure 1A and B. Although the structure appears to be stabilized by a hydrogen-bonding network involving N7:N2H and O6:N1H, this is unlikely to be the source of the thermodynamic stability of such structures in the solution state (see Thermodynamics and kinetics section). Indeed, the central core of the G-quartet produces a specific geometric arrangement of lone pairs of electrons from the four GO6, which can coordinate a monovalent ion of the correct size, such as Na+ or K+. Generally, these structures do not form in the absence of such ions. The smaller Na+ ion can sit in the plane formed by these atoms, whereas the larger K+ requires a nonplanar component, which may in fact lie between two such G-quartets, as shown in Figure 2. In fact, this allows additional coordination of the metal ions, i.e. to satisfy the usual hexacoordinate stereochemistry of the alkali metal ions. In order to accommodate this stereochemistry, the individual nucleobases may dome out of the plane somewhat (31), to an extent balanced by the stacking energies (see Thermodynamics and kinetics section for more detail).Figure 2.


Stability and kinetics of G-quadruplex structures.

Lane AN, Chaires JB, Gray RD, Trent JO - Nucleic Acids Res. (2008)

Stacked quartets with coordinated monovalent ion. (A) Parallel stacked quartets with Na+ stabilization (purple spheres) from (d(TGGGGT)4), (B) parallel stacked quartets with K+ stabilization (green spheres) from (dA(GGGTTA)3GGG), (C) d(TGGGGT)4 stacking in space filling representation, (D) dA(GGGTTA)3GGG stacking in space filling representation. Loops have been removed from C and D for clarity.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2553573&req=5

Figure 2: Stacked quartets with coordinated monovalent ion. (A) Parallel stacked quartets with Na+ stabilization (purple spheres) from (d(TGGGGT)4), (B) parallel stacked quartets with K+ stabilization (green spheres) from (dA(GGGTTA)3GGG), (C) d(TGGGGT)4 stacking in space filling representation, (D) dA(GGGTTA)3GGG stacking in space filling representation. Loops have been removed from C and D for clarity.
Mentions: G-quartets are based on the formation of a (nearly) square planar array of four guanine bases, as shown in Figure 1A and B. Although the structure appears to be stabilized by a hydrogen-bonding network involving N7:N2H and O6:N1H, this is unlikely to be the source of the thermodynamic stability of such structures in the solution state (see Thermodynamics and kinetics section). Indeed, the central core of the G-quartet produces a specific geometric arrangement of lone pairs of electrons from the four GO6, which can coordinate a monovalent ion of the correct size, such as Na+ or K+. Generally, these structures do not form in the absence of such ions. The smaller Na+ ion can sit in the plane formed by these atoms, whereas the larger K+ requires a nonplanar component, which may in fact lie between two such G-quartets, as shown in Figure 2. In fact, this allows additional coordination of the metal ions, i.e. to satisfy the usual hexacoordinate stereochemistry of the alkali metal ions. In order to accommodate this stereochemistry, the individual nucleobases may dome out of the plane somewhat (31), to an extent balanced by the stacking energies (see Thermodynamics and kinetics section for more detail).Figure 2.

Bottom Line: Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes.Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium.The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology Program, JG Brown Cancer Center, University of Louisville, KY 40202, USA. anlane01@gwise.louisville.edu

ABSTRACT
In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

Show MeSH