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Probing the structural hierarchy and energy landscape of an RNA T-loop hairpin.

Zhuang Z, Jaeger L, Shea JE - Nucleic Acids Res. (2007)

Bottom Line: On the other hand, the stability of the UA non-canonical base pair is enhanced in the presence of the UA-handle.This motif is apparently a key component for stabilizing the T-loop, while the U-turn is mostly involved in long-range interaction.Our results suggest that the stability and folding of small RNA motifs are highly dependent on local context.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA.

ABSTRACT
The T-loop motif is an important recurrent RNA structural building block consisting of a U-turn sub-motif and a UA trans Watson-Crick/Hoogsteen base pair. In the presence of a hairpin stem, the UA non-canonical base pair becomes part of the UA-handle motif. To probe the hierarchical organization and energy landscape of the T-loop, we performed replica exchange molecular dynamics (REMD) simulations of the T-loop in isolation and as part of a hairpin. Our simulations reveal that the isolated T-loop adopts coil conformers stabilized by base stacking. The T-loop hairpin shows a highly rugged energy landscape featuring multiple local minima with a transition state for folding consisting of partially zipped states. The U-turn displays a high conformational flexibility both when the T-loop is in isolation and as part of a hairpin. On the other hand, the stability of the UA non-canonical base pair is enhanced in the presence of the UA-handle. This motif is apparently a key component for stabilizing the T-loop, while the U-turn is mostly involved in long-range interaction. Our results suggest that the stability and folding of small RNA motifs are highly dependent on local context.

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T-loop RNA hairpin with its components: (A) sequence signature of the U-turn sub-motif, the U:A trans W/H bp, the UA-handle and the T-loop. The UA-handle motif comprises at least 5 nt that form a U:A trans W/H bp, a WC pb and a bulge. N stands for any nucleotides (G, A, U or C); R stands for purine (G or A); Y stands for pyrimidine (U or C). (B) Sequence of the motifs simulated in this study, which includes the U-turn motif, the closing U:A trans W/H bp, the single nucleotide C in bulge, the UA-handle and the hairpin stem. (C) 3D structures of the corresponding model systems in their crystal conformation. The trans W/H base pair is indicated according to the nomenclature of base pairs defined by Leontis and Westhof (60).
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Figure 1: T-loop RNA hairpin with its components: (A) sequence signature of the U-turn sub-motif, the U:A trans W/H bp, the UA-handle and the T-loop. The UA-handle motif comprises at least 5 nt that form a U:A trans W/H bp, a WC pb and a bulge. N stands for any nucleotides (G, A, U or C); R stands for purine (G or A); Y stands for pyrimidine (U or C). (B) Sequence of the motifs simulated in this study, which includes the U-turn motif, the closing U:A trans W/H bp, the single nucleotide C in bulge, the UA-handle and the hairpin stem. (C) 3D structures of the corresponding model systems in their crystal conformation. The trans W/H base pair is indicated according to the nomenclature of base pairs defined by Leontis and Westhof (60).

Mentions: In this study, we present all-atom explicit solvent simulations of the T-loop using an enhanced sampling technique known as replica exchange molecular dynamics simulations (REMD) (43–45). The T-loop studied here consists of the U-turn sub-motif often found in the GNRA tetraloop, the U-A trans W/H closing bp, and a single nucleotide bulge at the 3′ end of the conserved adenine (Figure 1). The hairpin includes the T-loop and a 3-bp long stem. When the U:A trans W/H bp is stacked on a WC bp in the presence of a hairpin stem, a new motif called the UA-handle is created (Verzemnieks and Jaeger, manuscript in preparation). Consequently, our model system can be decomposed into many different subunits/components and it represents a minimal RNA structure with realistic hierarchical organization that is amenable to computational studies (Figure 1).Figure 1.


Probing the structural hierarchy and energy landscape of an RNA T-loop hairpin.

Zhuang Z, Jaeger L, Shea JE - Nucleic Acids Res. (2007)

T-loop RNA hairpin with its components: (A) sequence signature of the U-turn sub-motif, the U:A trans W/H bp, the UA-handle and the T-loop. The UA-handle motif comprises at least 5 nt that form a U:A trans W/H bp, a WC pb and a bulge. N stands for any nucleotides (G, A, U or C); R stands for purine (G or A); Y stands for pyrimidine (U or C). (B) Sequence of the motifs simulated in this study, which includes the U-turn motif, the closing U:A trans W/H bp, the single nucleotide C in bulge, the UA-handle and the hairpin stem. (C) 3D structures of the corresponding model systems in their crystal conformation. The trans W/H base pair is indicated according to the nomenclature of base pairs defined by Leontis and Westhof (60).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2175325&req=5

Figure 1: T-loop RNA hairpin with its components: (A) sequence signature of the U-turn sub-motif, the U:A trans W/H bp, the UA-handle and the T-loop. The UA-handle motif comprises at least 5 nt that form a U:A trans W/H bp, a WC pb and a bulge. N stands for any nucleotides (G, A, U or C); R stands for purine (G or A); Y stands for pyrimidine (U or C). (B) Sequence of the motifs simulated in this study, which includes the U-turn motif, the closing U:A trans W/H bp, the single nucleotide C in bulge, the UA-handle and the hairpin stem. (C) 3D structures of the corresponding model systems in their crystal conformation. The trans W/H base pair is indicated according to the nomenclature of base pairs defined by Leontis and Westhof (60).
Mentions: In this study, we present all-atom explicit solvent simulations of the T-loop using an enhanced sampling technique known as replica exchange molecular dynamics simulations (REMD) (43–45). The T-loop studied here consists of the U-turn sub-motif often found in the GNRA tetraloop, the U-A trans W/H closing bp, and a single nucleotide bulge at the 3′ end of the conserved adenine (Figure 1). The hairpin includes the T-loop and a 3-bp long stem. When the U:A trans W/H bp is stacked on a WC bp in the presence of a hairpin stem, a new motif called the UA-handle is created (Verzemnieks and Jaeger, manuscript in preparation). Consequently, our model system can be decomposed into many different subunits/components and it represents a minimal RNA structure with realistic hierarchical organization that is amenable to computational studies (Figure 1).Figure 1.

Bottom Line: On the other hand, the stability of the UA non-canonical base pair is enhanced in the presence of the UA-handle.This motif is apparently a key component for stabilizing the T-loop, while the U-turn is mostly involved in long-range interaction.Our results suggest that the stability and folding of small RNA motifs are highly dependent on local context.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA.

ABSTRACT
The T-loop motif is an important recurrent RNA structural building block consisting of a U-turn sub-motif and a UA trans Watson-Crick/Hoogsteen base pair. In the presence of a hairpin stem, the UA non-canonical base pair becomes part of the UA-handle motif. To probe the hierarchical organization and energy landscape of the T-loop, we performed replica exchange molecular dynamics (REMD) simulations of the T-loop in isolation and as part of a hairpin. Our simulations reveal that the isolated T-loop adopts coil conformers stabilized by base stacking. The T-loop hairpin shows a highly rugged energy landscape featuring multiple local minima with a transition state for folding consisting of partially zipped states. The U-turn displays a high conformational flexibility both when the T-loop is in isolation and as part of a hairpin. On the other hand, the stability of the UA non-canonical base pair is enhanced in the presence of the UA-handle. This motif is apparently a key component for stabilizing the T-loop, while the U-turn is mostly involved in long-range interaction. Our results suggest that the stability and folding of small RNA motifs are highly dependent on local context.

Show MeSH