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ModeRNA: a tool for comparative modeling of RNA 3D structure.

Rother M, Rother K, Puton T, Bujnicki JM - Nucleic Acids Res. (2011)

Bottom Line: It must be emphasized that a good alignment is required for successful modeling, and for large and complex RNA molecules the development of a good alignment usually requires manual adjustments of the input data based on previous expertise of the respective RNA family.It is equipped with many functions for merging fragments of different nucleic acid structures into a single model and analyzing their geometry.Windows and UNIX implementations of ModeRNA with comprehensive documentation and a tutorial are freely available.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul Ks Trojdena 4, 02-109 Warsaw, Poland.

ABSTRACT
RNA is a large group of functionally important biomacromolecules. In striking analogy to proteins, the function of RNA depends on its structure and dynamics, which in turn is encoded in the linear sequence. However, while there are numerous methods for computational prediction of protein three-dimensional (3D) structure from sequence, with comparative modeling being the most reliable approach, there are very few such methods for RNA. Here, we present ModeRNA, a software tool for comparative modeling of RNA 3D structures. As an input, ModeRNA requires a 3D structure of a template RNA molecule, and a sequence alignment between the target to be modeled and the template. It must be emphasized that a good alignment is required for successful modeling, and for large and complex RNA molecules the development of a good alignment usually requires manual adjustments of the input data based on previous expertise of the respective RNA family. ModeRNA can model post-transcriptional modifications, a functionally important feature analogous to post-translational modifications in proteins. ModeRNA can also model DNA structures or use them as templates. It is equipped with many functions for merging fragments of different nucleic acid structures into a single model and analyzing their geometry. Windows and UNIX implementations of ModeRNA with comprehensive documentation and a tutorial are freely available.

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Examples of models built by ModeRNA. Models are shown in red, the native structure is shown in green. (a) Model of E. coli tRNAPhe (native structure 2J00_W) built on the target 2HGP_D (E. coli tRNAPhe). The sequences of both molecules are 100% identical, the RMSD value is relatively high—3.61. The residues that contribute the most in the high RMSD are marked with gray clouds and their conformation is shown in separate boxes. (b) Model of E. coli tRNAThr (the native structure 1QF6_B—PDB-ID 1QF6, chain B) built on the template 1B23_R E. coli tRNACys. The native structure is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu-shifting the conformation of the acceptor stem and anticodon loop by several Å, both regions are marked by gray clouds. (c) Model of E. coli tRNAfMet (native structure 2HGI_C) built on the template 2B64_V (E. coli tRNAPhe). Model structure has low RMSD—1.38 Å despite medium sequence similarity (47%) between the target and the template molecule. (d) Model of tRNAGlu (native structure 2DXI_C) built on 2DET. Both structures have a high-sequence similarity (72%). Yet, the RMSD amounts 8.05 Å. The reason is the 6 nt long fragment that is missing in the template on the 3′ end. In the model it has a completely different conformation than the native one. (e) Adenine-binding riboswitch (1Y26) modeled using a guanine-binding riboswitch (1Y27). (f) 30S ribosomal subunits from T. thermophilus (1J5E_A) modeled using 30S from E. coli (2AVY_A). Three regions where the model did not match the native PDB structure well are highlighted: I—two hairpins connected by a junction (residues 970–1022), II—stem loop (residues 65–89), III—stem loop (residues 173–196).
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Figure 3: Examples of models built by ModeRNA. Models are shown in red, the native structure is shown in green. (a) Model of E. coli tRNAPhe (native structure 2J00_W) built on the target 2HGP_D (E. coli tRNAPhe). The sequences of both molecules are 100% identical, the RMSD value is relatively high—3.61. The residues that contribute the most in the high RMSD are marked with gray clouds and their conformation is shown in separate boxes. (b) Model of E. coli tRNAThr (the native structure 1QF6_B—PDB-ID 1QF6, chain B) built on the template 1B23_R E. coli tRNACys. The native structure is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu-shifting the conformation of the acceptor stem and anticodon loop by several Å, both regions are marked by gray clouds. (c) Model of E. coli tRNAfMet (native structure 2HGI_C) built on the template 2B64_V (E. coli tRNAPhe). Model structure has low RMSD—1.38 Å despite medium sequence similarity (47%) between the target and the template molecule. (d) Model of tRNAGlu (native structure 2DXI_C) built on 2DET. Both structures have a high-sequence similarity (72%). Yet, the RMSD amounts 8.05 Å. The reason is the 6 nt long fragment that is missing in the template on the 3′ end. In the model it has a completely different conformation than the native one. (e) Adenine-binding riboswitch (1Y26) modeled using a guanine-binding riboswitch (1Y27). (f) 30S ribosomal subunits from T. thermophilus (1J5E_A) modeled using 30S from E. coli (2AVY_A). Three regions where the model did not match the native PDB structure well are highlighted: I—two hairpins connected by a junction (residues 970–1022), II—stem loop (residues 65–89), III—stem loop (residues 173–196).

Mentions: The acceptor stem and the anticodon loop of tRNA are known to be highly flexible and to change their conformation upon complex formation with proteins (e.g. enzymes acting on tRNA) or in the ribosome (47). This can be observed in the model of the ribosome-bound E. coli tRNAPhe 2J00_W (PDB-ID 2J00, chain W) built on the template 2HGP_D (Figure 3), where the ribosome is in post-initiation conformation. The resulting all-atom RMSD is as high as 3.6 Å despite the two molecules have 100% identical sequences. This high RMSD value is mostly caused by residues 17 (RMSD = 8.5) and 47 (RMSD = 6.7), where the bases have different orientations in the model and in the native structure, and the two residues preceding the CCA 3′-end. A similar observation can be made for the model of E. coli tRNAThr built on E. coli tRNAPhe (1B23_R) as the template (Figure 3). The native structure of tRNAThr (1QF6_B) is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu, resulting in a mutual shift of the acceptor stem and the anticodon loop by several Å. This illustrates that the accuracy of comparative models of tRNAs (and by extension—all RNAs) is limited by availability and correct choice of a template in an appropriate physiological state. However, we must emphasize that as with proteins, the problem of template selection is to a large extent independent from the actual process of model building.Figure 3.


ModeRNA: a tool for comparative modeling of RNA 3D structure.

Rother M, Rother K, Puton T, Bujnicki JM - Nucleic Acids Res. (2011)

Examples of models built by ModeRNA. Models are shown in red, the native structure is shown in green. (a) Model of E. coli tRNAPhe (native structure 2J00_W) built on the target 2HGP_D (E. coli tRNAPhe). The sequences of both molecules are 100% identical, the RMSD value is relatively high—3.61. The residues that contribute the most in the high RMSD are marked with gray clouds and their conformation is shown in separate boxes. (b) Model of E. coli tRNAThr (the native structure 1QF6_B—PDB-ID 1QF6, chain B) built on the template 1B23_R E. coli tRNACys. The native structure is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu-shifting the conformation of the acceptor stem and anticodon loop by several Å, both regions are marked by gray clouds. (c) Model of E. coli tRNAfMet (native structure 2HGI_C) built on the template 2B64_V (E. coli tRNAPhe). Model structure has low RMSD—1.38 Å despite medium sequence similarity (47%) between the target and the template molecule. (d) Model of tRNAGlu (native structure 2DXI_C) built on 2DET. Both structures have a high-sequence similarity (72%). Yet, the RMSD amounts 8.05 Å. The reason is the 6 nt long fragment that is missing in the template on the 3′ end. In the model it has a completely different conformation than the native one. (e) Adenine-binding riboswitch (1Y26) modeled using a guanine-binding riboswitch (1Y27). (f) 30S ribosomal subunits from T. thermophilus (1J5E_A) modeled using 30S from E. coli (2AVY_A). Three regions where the model did not match the native PDB structure well are highlighted: I—two hairpins connected by a junction (residues 970–1022), II—stem loop (residues 65–89), III—stem loop (residues 173–196).
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Figure 3: Examples of models built by ModeRNA. Models are shown in red, the native structure is shown in green. (a) Model of E. coli tRNAPhe (native structure 2J00_W) built on the target 2HGP_D (E. coli tRNAPhe). The sequences of both molecules are 100% identical, the RMSD value is relatively high—3.61. The residues that contribute the most in the high RMSD are marked with gray clouds and their conformation is shown in separate boxes. (b) Model of E. coli tRNAThr (the native structure 1QF6_B—PDB-ID 1QF6, chain B) built on the template 1B23_R E. coli tRNACys. The native structure is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu-shifting the conformation of the acceptor stem and anticodon loop by several Å, both regions are marked by gray clouds. (c) Model of E. coli tRNAfMet (native structure 2HGI_C) built on the template 2B64_V (E. coli tRNAPhe). Model structure has low RMSD—1.38 Å despite medium sequence similarity (47%) between the target and the template molecule. (d) Model of tRNAGlu (native structure 2DXI_C) built on 2DET. Both structures have a high-sequence similarity (72%). Yet, the RMSD amounts 8.05 Å. The reason is the 6 nt long fragment that is missing in the template on the 3′ end. In the model it has a completely different conformation than the native one. (e) Adenine-binding riboswitch (1Y26) modeled using a guanine-binding riboswitch (1Y27). (f) 30S ribosomal subunits from T. thermophilus (1J5E_A) modeled using 30S from E. coli (2AVY_A). Three regions where the model did not match the native PDB structure well are highlighted: I—two hairpins connected by a junction (residues 970–1022), II—stem loop (residues 65–89), III—stem loop (residues 173–196).
Mentions: The acceptor stem and the anticodon loop of tRNA are known to be highly flexible and to change their conformation upon complex formation with proteins (e.g. enzymes acting on tRNA) or in the ribosome (47). This can be observed in the model of the ribosome-bound E. coli tRNAPhe 2J00_W (PDB-ID 2J00, chain W) built on the template 2HGP_D (Figure 3), where the ribosome is in post-initiation conformation. The resulting all-atom RMSD is as high as 3.6 Å despite the two molecules have 100% identical sequences. This high RMSD value is mostly caused by residues 17 (RMSD = 8.5) and 47 (RMSD = 6.7), where the bases have different orientations in the model and in the native structure, and the two residues preceding the CCA 3′-end. A similar observation can be made for the model of E. coli tRNAThr built on E. coli tRNAPhe (1B23_R) as the template (Figure 3). The native structure of tRNAThr (1QF6_B) is interacting with threonyl-tRNA synthetase, while the template structure is in contact with the translation elongation factor EF-Tu, resulting in a mutual shift of the acceptor stem and the anticodon loop by several Å. This illustrates that the accuracy of comparative models of tRNAs (and by extension—all RNAs) is limited by availability and correct choice of a template in an appropriate physiological state. However, we must emphasize that as with proteins, the problem of template selection is to a large extent independent from the actual process of model building.Figure 3.

Bottom Line: It must be emphasized that a good alignment is required for successful modeling, and for large and complex RNA molecules the development of a good alignment usually requires manual adjustments of the input data based on previous expertise of the respective RNA family.It is equipped with many functions for merging fragments of different nucleic acid structures into a single model and analyzing their geometry.Windows and UNIX implementations of ModeRNA with comprehensive documentation and a tutorial are freely available.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul Ks Trojdena 4, 02-109 Warsaw, Poland.

ABSTRACT
RNA is a large group of functionally important biomacromolecules. In striking analogy to proteins, the function of RNA depends on its structure and dynamics, which in turn is encoded in the linear sequence. However, while there are numerous methods for computational prediction of protein three-dimensional (3D) structure from sequence, with comparative modeling being the most reliable approach, there are very few such methods for RNA. Here, we present ModeRNA, a software tool for comparative modeling of RNA 3D structures. As an input, ModeRNA requires a 3D structure of a template RNA molecule, and a sequence alignment between the target to be modeled and the template. It must be emphasized that a good alignment is required for successful modeling, and for large and complex RNA molecules the development of a good alignment usually requires manual adjustments of the input data based on previous expertise of the respective RNA family. ModeRNA can model post-transcriptional modifications, a functionally important feature analogous to post-translational modifications in proteins. ModeRNA can also model DNA structures or use them as templates. It is equipped with many functions for merging fragments of different nucleic acid structures into a single model and analyzing their geometry. Windows and UNIX implementations of ModeRNA with comprehensive documentation and a tutorial are freely available.

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