Limits...
Explaining the varied glycosidic conformational, G-tract length and sequence preferences for anti-parallel G-quadruplexes.

Cang X, Šponer J, Cheatham TE - Nucleic Acids Res. (2011)

Bottom Line: Structural polymorphisms of G-quadruplexes relate to these glycosidic conformational patterns and the lengths of the G-tracts.G3-tracts, on the other hand, cannot present this repeating pattern on each G-tract.This leads to smaller energy differences between different geometries and helps explain the extreme structural polymorphism of the human telomeric G-quadruplexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.

ABSTRACT
Guanine-rich DNA sequences tend to form four-stranded G-quadruplex structures. Characteristic glycosidic conformational patterns along the G-strands, such as the 5'-syn-anti-syn-anti pattern observed with the Oxytricha nova telomeric G-quadruplexes, have been well documented. However, an explanation for these featured glycosidic patterns has not emerged. This work presents MD simulation and free energetic analyses for simplified two-quartet [d(GG)](4) models and suggests that the four base pair step patterns show quite different relative stabilities: syn-anti > anti-anti > anti-syn > syn-syn. This suggests the following rule: when folding, anti-parallel G-quadruplexes tend to maximize the number of syn-anti steps and avoid the unfavorable anti-syn and syn-syn steps. This rule is consistent with most of the anti-parallel G-quadruplex structures in the Protein Databank (PDB). Structural polymorphisms of G-quadruplexes relate to these glycosidic conformational patterns and the lengths of the G-tracts. The folding topologies of G2- and G4-tracts are not very polymorphic because each strand tends to populate the stable syn-anti repeat. G3-tracts, on the other hand, cannot present this repeating pattern on each G-tract. This leads to smaller energy differences between different geometries and helps explain the extreme structural polymorphism of the human telomeric G-quadruplexes.

Show MeSH
Molecular graphics highlighting the hydrogen bond formed with a high occupancy within the 5′-terminal syn guanosine during the MD simulation.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3105399&req=5

Figure 3: Molecular graphics highlighting the hydrogen bond formed with a high occupancy within the 5′-terminal syn guanosine during the MD simulation.

Mentions: As anti-anti steps are dominant in the DNA double helix, the AA model was used as a reference to calculate the relative free energy of each model. Surprisingly, the free energy results suggest that the SA models are significantly more stable than the AA model. The differences in estimated free energies are large (−32 kcal/mol) and dominated by the internal (bond, angle and dihedral) and electrostatic free energy contributions. Much of this overstabilization is due to hydrogen bonds at the 5′ syn-dG due to the dangling ends (see the ΔG† values in Table 1). When the 5′-terminal guanine has a syn glycosidic bond orientation, a hydrogen bond between O5′-H···N3 will form with a high occupancy during the MD simulations (Figure 3); this is not observed when the 5′-terminal guanine has an anti glycosidic bond orientation. Similar hydrogen bonding is also observed in experimental structures with at most one 5′-dG syn O5′-H···N3 hydrogen bond in monomeric anti-parallel quadruplexes and two in the dimeric anti-parallel quadruplexes. The simple two-quartet models studied here introduce more 5′-ends because of the absence of connecting loops. The SA models have four O5′-H5T···N3 hydrogen bonds that bring extra stability to the system; however, this is not representative of the native folded quadruplex structures generated from a single contiguous sequence. To exclude these contributions, we ran an additional simulation on the SA-aabb model with a restraint to prevent the formation of the O5′-H···N3 hydrogen bonds (referred to as SA-aabb-r). A lower bound restraint distance of 3.5 Å with a force constant of 5 kcal/(mol • Å2) was applied to the H5T and N3 atoms at each of the four 5′-ends. A stable MD trajectory over 33 ns was observed, and the last 10 ns was used to estimate MM-PBSA energetics calculated at 200-ps intervals. The restrained SA-aabb-r model is now −14.5 kcal/mol (−3.6 kcal/mol per strand) more stable than the AA model. Additionally, we recalculated the energetics omitting these hydrogen bonds with the three unrestrained SA trajectories and similar results are obtained. The free energetic results suggest that the four 5′-end hydrogen bonds in total contribute −17.7 kcal/mol to the free energy of the SA-aabb model, i.e. −4.4 kcal/mol for each hydrogen bond. When these dangling end hydrogen bonds are omitted, a more reasonable ∼4 kcal/mol per strand difference is obtained. The large values are in part due to the approximate nature of the MM-PBSA method, and it is common with MM-PBSA to reproduce the correct free energy trends yet tend to overestimate the absolute values of free energy differences (49).Figure 3.


Explaining the varied glycosidic conformational, G-tract length and sequence preferences for anti-parallel G-quadruplexes.

Cang X, Šponer J, Cheatham TE - Nucleic Acids Res. (2011)

Molecular graphics highlighting the hydrogen bond formed with a high occupancy within the 5′-terminal syn guanosine during the MD simulation.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105399&req=5

Figure 3: Molecular graphics highlighting the hydrogen bond formed with a high occupancy within the 5′-terminal syn guanosine during the MD simulation.
Mentions: As anti-anti steps are dominant in the DNA double helix, the AA model was used as a reference to calculate the relative free energy of each model. Surprisingly, the free energy results suggest that the SA models are significantly more stable than the AA model. The differences in estimated free energies are large (−32 kcal/mol) and dominated by the internal (bond, angle and dihedral) and electrostatic free energy contributions. Much of this overstabilization is due to hydrogen bonds at the 5′ syn-dG due to the dangling ends (see the ΔG† values in Table 1). When the 5′-terminal guanine has a syn glycosidic bond orientation, a hydrogen bond between O5′-H···N3 will form with a high occupancy during the MD simulations (Figure 3); this is not observed when the 5′-terminal guanine has an anti glycosidic bond orientation. Similar hydrogen bonding is also observed in experimental structures with at most one 5′-dG syn O5′-H···N3 hydrogen bond in monomeric anti-parallel quadruplexes and two in the dimeric anti-parallel quadruplexes. The simple two-quartet models studied here introduce more 5′-ends because of the absence of connecting loops. The SA models have four O5′-H5T···N3 hydrogen bonds that bring extra stability to the system; however, this is not representative of the native folded quadruplex structures generated from a single contiguous sequence. To exclude these contributions, we ran an additional simulation on the SA-aabb model with a restraint to prevent the formation of the O5′-H···N3 hydrogen bonds (referred to as SA-aabb-r). A lower bound restraint distance of 3.5 Å with a force constant of 5 kcal/(mol • Å2) was applied to the H5T and N3 atoms at each of the four 5′-ends. A stable MD trajectory over 33 ns was observed, and the last 10 ns was used to estimate MM-PBSA energetics calculated at 200-ps intervals. The restrained SA-aabb-r model is now −14.5 kcal/mol (−3.6 kcal/mol per strand) more stable than the AA model. Additionally, we recalculated the energetics omitting these hydrogen bonds with the three unrestrained SA trajectories and similar results are obtained. The free energetic results suggest that the four 5′-end hydrogen bonds in total contribute −17.7 kcal/mol to the free energy of the SA-aabb model, i.e. −4.4 kcal/mol for each hydrogen bond. When these dangling end hydrogen bonds are omitted, a more reasonable ∼4 kcal/mol per strand difference is obtained. The large values are in part due to the approximate nature of the MM-PBSA method, and it is common with MM-PBSA to reproduce the correct free energy trends yet tend to overestimate the absolute values of free energy differences (49).Figure 3.

Bottom Line: Structural polymorphisms of G-quadruplexes relate to these glycosidic conformational patterns and the lengths of the G-tracts.G3-tracts, on the other hand, cannot present this repeating pattern on each G-tract.This leads to smaller energy differences between different geometries and helps explain the extreme structural polymorphism of the human telomeric G-quadruplexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.

ABSTRACT
Guanine-rich DNA sequences tend to form four-stranded G-quadruplex structures. Characteristic glycosidic conformational patterns along the G-strands, such as the 5'-syn-anti-syn-anti pattern observed with the Oxytricha nova telomeric G-quadruplexes, have been well documented. However, an explanation for these featured glycosidic patterns has not emerged. This work presents MD simulation and free energetic analyses for simplified two-quartet [d(GG)](4) models and suggests that the four base pair step patterns show quite different relative stabilities: syn-anti > anti-anti > anti-syn > syn-syn. This suggests the following rule: when folding, anti-parallel G-quadruplexes tend to maximize the number of syn-anti steps and avoid the unfavorable anti-syn and syn-syn steps. This rule is consistent with most of the anti-parallel G-quadruplex structures in the Protein Databank (PDB). Structural polymorphisms of G-quadruplexes relate to these glycosidic conformational patterns and the lengths of the G-tracts. The folding topologies of G2- and G4-tracts are not very polymorphic because each strand tends to populate the stable syn-anti repeat. G3-tracts, on the other hand, cannot present this repeating pattern on each G-tract. This leads to smaller energy differences between different geometries and helps explain the extreme structural polymorphism of the human telomeric G-quadruplexes.

Show MeSH