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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.

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Cartoons of the three-quartet and four-quartet stem models tested in this work are shown: (a) 3SAA + 1SSA, (b) AAA, (c) SAA-parallel, (d) ASA-parallel, (e) SASA and (f) AAAA. Yellow is for syn and blue is for anti glycosidic bond orientations. The channel cations (K+) present in the models and simulations are not shown. Note that because the original backbone geometry of the anti-syn steps in the SASA model were not maintained in the MD simulations, restraints were applied to the α/γ angles of the anti-syn steps in a manner similar to those applied with the two-quartet models. The MD simulations on these stem models all produced very stable trajectories. With the three-quartet models, the two channel-K+ maintained their positions throughout all the simulations. With the four-quartet models, the three channel-K+ are more mobile and two main channel cation arrangements were observed: either all three K+ within the channel, or two K+ in the channel and one K+ located at the channel entrance.
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Figure 5: Cartoons of the three-quartet and four-quartet stem models tested in this work are shown: (a) 3SAA + 1SSA, (b) AAA, (c) SAA-parallel, (d) ASA-parallel, (e) SASA and (f) AAAA. Yellow is for syn and blue is for anti glycosidic bond orientations. The channel cations (K+) present in the models and simulations are not shown. Note that because the original backbone geometry of the anti-syn steps in the SASA model were not maintained in the MD simulations, restraints were applied to the α/γ angles of the anti-syn steps in a manner similar to those applied with the two-quartet models. The MD simulations on these stem models all produced very stable trajectories. With the three-quartet models, the two channel-K+ maintained their positions throughout all the simulations. With the four-quartet models, the three channel-K+ are more mobile and two main channel cation arrangements were observed: either all three K+ within the channel, or two K+ in the channel and one K+ located at the channel entrance.

Mentions: The two-quartet models applied in this work are very simplified models for MD simulations; they were used to get reasonable and straightforward energetic estimates for the four glycosidic steps. To test whether the same trends are maintained in the stems of more quartet layers, similar work investigated various three-quartet and four-quartet stem models (Figure 5). The (3SAA + 1SSA) model was built from the human telomeric G-quadruplex 2GKU (34); AAA was built from the first three G-quartets of the NMR parallel structure 139D (35). A model with four parallel syn-ant-anti strands (SAA-parallel) was also built based on the previous NMR experiments indicating that [d(TGMeGGT)]4 form a parallel quadruplex possessing an all syn quartet (52). The (3SAA + 1SSA) model was used as the template to build the SAA-parallel model through UCSF Chimera (53). In this SAA-parallel model, only syn-anti and anti-anti steps exist, therefore comparison to the AAA model was straightforward. The four-quartet parallel and anti-parallel stem models were built from the G-quartets of the structures 139D and 1JPQ (33), respectively. Additional three-quartet stem models were investigated; however, the anti-syn and syn-syn steps in these models lost the original backbone α/γ geometry during the simulation equilibration steps, so these results are not shown here.Figure 5.


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)

Cartoons of the three-quartet and four-quartet stem models tested in this work are shown: (a) 3SAA + 1SSA, (b) AAA, (c) SAA-parallel, (d) ASA-parallel, (e) SASA and (f) AAAA. Yellow is for syn and blue is for anti glycosidic bond orientations. The channel cations (K+) present in the models and simulations are not shown. Note that because the original backbone geometry of the anti-syn steps in the SASA model were not maintained in the MD simulations, restraints were applied to the α/γ angles of the anti-syn steps in a manner similar to those applied with the two-quartet models. The MD simulations on these stem models all produced very stable trajectories. With the three-quartet models, the two channel-K+ maintained their positions throughout all the simulations. With the four-quartet models, the three channel-K+ are more mobile and two main channel cation arrangements were observed: either all three K+ within the channel, or two K+ in the channel and one K+ located at the channel entrance.
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Related In: Results  -  Collection

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Figure 5: Cartoons of the three-quartet and four-quartet stem models tested in this work are shown: (a) 3SAA + 1SSA, (b) AAA, (c) SAA-parallel, (d) ASA-parallel, (e) SASA and (f) AAAA. Yellow is for syn and blue is for anti glycosidic bond orientations. The channel cations (K+) present in the models and simulations are not shown. Note that because the original backbone geometry of the anti-syn steps in the SASA model were not maintained in the MD simulations, restraints were applied to the α/γ angles of the anti-syn steps in a manner similar to those applied with the two-quartet models. The MD simulations on these stem models all produced very stable trajectories. With the three-quartet models, the two channel-K+ maintained their positions throughout all the simulations. With the four-quartet models, the three channel-K+ are more mobile and two main channel cation arrangements were observed: either all three K+ within the channel, or two K+ in the channel and one K+ located at the channel entrance.
Mentions: The two-quartet models applied in this work are very simplified models for MD simulations; they were used to get reasonable and straightforward energetic estimates for the four glycosidic steps. To test whether the same trends are maintained in the stems of more quartet layers, similar work investigated various three-quartet and four-quartet stem models (Figure 5). The (3SAA + 1SSA) model was built from the human telomeric G-quadruplex 2GKU (34); AAA was built from the first three G-quartets of the NMR parallel structure 139D (35). A model with four parallel syn-ant-anti strands (SAA-parallel) was also built based on the previous NMR experiments indicating that [d(TGMeGGT)]4 form a parallel quadruplex possessing an all syn quartet (52). The (3SAA + 1SSA) model was used as the template to build the SAA-parallel model through UCSF Chimera (53). In this SAA-parallel model, only syn-anti and anti-anti steps exist, therefore comparison to the AAA model was straightforward. The four-quartet parallel and anti-parallel stem models were built from the G-quartets of the structures 139D and 1JPQ (33), respectively. Additional three-quartet stem models were investigated; however, the anti-syn and syn-syn steps in these models lost the original backbone α/γ geometry during the simulation equilibration steps, so these results are not shown here.Figure 5.

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.

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