Limits...
Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore.

Dickson A, Mustoe AM, Salmon L, Brooks CL - Nucleic Acids Res. (2014)

Bottom Line: Our ensemble achieves similar agreement with experimental NMR data when compared with previous TAR computational studies, and is generated at a fraction of the computational cost.It clearly emerges from configuration space network analysis that the intermittent formation of the A22-U40 base pair acts as a reversible switch that enables sampling of interhelical conformations that would otherwise be topologically disallowed.We find that most previously determined ligand-bound structures are found in similar location in the network, and we use a sample-and-select approach to guide the construction of a set of novel conformations which can serve as the basis for future drug development efforts.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Michigan, 930 N University, Ann Arbor, MI 48109, USA.

Show MeSH
Mapping ligand-bound structures on the TAR CSN. For each ligand-bound structure, we show a CSN for TAR with the node colorings indicating the distance in Euler angle space from each node to the ligand-bound structure. For NMR structures with multiple models, we plot the distance to the first model in the structure. Nodes that are greater than 50° are colored blue, and red nodes reveal structures that are close to the ligand-bound structure. Each plot is labeled by the name of the inhibitor molecule, except for PDBID:2L8H (23), which shows the bound structure of arginine 4-methoxy-naphthylamide. The PDB indices for the other bound structures are as follows: ADP-1 (1ARJ (70)), Neomycin B (1QD3 (17)), KP-Z-41 (2KX5 (22)), L-22 (2KDQ (21)), RBT203 (1UUD (19)), Acetylpromazine (1LVJ (18)), RBT158 (1UUI (19)), RBT550 (1UTS (20)). Insets are shown that focus on the nodes that are closest to the bound structure, and the number below each shows the closest distance to the bound structure. The plots are sorted by the overall closest distance, and range from 23° for ADP-1 to 5.6° for Acetylpromazine. The insets are connected to transparent green circles in each network that show the area prior to magnification. Color figure is available online.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4231733&req=5

Figure 6: Mapping ligand-bound structures on the TAR CSN. For each ligand-bound structure, we show a CSN for TAR with the node colorings indicating the distance in Euler angle space from each node to the ligand-bound structure. For NMR structures with multiple models, we plot the distance to the first model in the structure. Nodes that are greater than 50° are colored blue, and red nodes reveal structures that are close to the ligand-bound structure. Each plot is labeled by the name of the inhibitor molecule, except for PDBID:2L8H (23), which shows the bound structure of arginine 4-methoxy-naphthylamide. The PDB indices for the other bound structures are as follows: ADP-1 (1ARJ (70)), Neomycin B (1QD3 (17)), KP-Z-41 (2KX5 (22)), L-22 (2KDQ (21)), RBT203 (1UUD (19)), Acetylpromazine (1LVJ (18)), RBT158 (1UUI (19)), RBT550 (1UTS (20)). Insets are shown that focus on the nodes that are closest to the bound structure, and the number below each shows the closest distance to the bound structure. The plots are sorted by the overall closest distance, and range from 23° for ADP-1 to 5.6° for Acetylpromazine. The insets are connected to transparent green circles in each network that show the area prior to magnification. Color figure is available online.

Mentions: HIV-1 TAR RNA plays a critical role in the infectivity of HIV; after it is transcribed by RNA Pol II, it binds the viral Tat and host Cyclin T1 proteins that are vital for promoting efficient transcription of the downstream HIV genome (14–16). As such, much work has focused on developing inhibitors of the interaction between TAR and Tat (17–23,70). In Figure 6, we map a set of known structures of TAR with inhibitors bound. For the four bound complexes shown at the top of Figure 6, there only exist a few states that are close to the bound structure, and they are not significantly populated as determined by the sampling in WExplore. Although this might suggest a binding mechanism of induced fit, an alternative explanation is that these conformations are significantly populated in the dynamics of TAR, but are simply not populated here due to insufficient sampling. Consistent with our discussion above, these four complexes have near-coaxial interhelical conformations (βh = 3.8°, 7.2°, 3.0° and 7.5°, for ADP-1, Neomycin B, 2L8H and KP-Z-41, respectively). Note that we are using a Euler distance of 20° to define the smallest regions in WExplore, so a distance of greater than 20° can be considered to be not sampled by our ensemble.


Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore.

Dickson A, Mustoe AM, Salmon L, Brooks CL - Nucleic Acids Res. (2014)

Mapping ligand-bound structures on the TAR CSN. For each ligand-bound structure, we show a CSN for TAR with the node colorings indicating the distance in Euler angle space from each node to the ligand-bound structure. For NMR structures with multiple models, we plot the distance to the first model in the structure. Nodes that are greater than 50° are colored blue, and red nodes reveal structures that are close to the ligand-bound structure. Each plot is labeled by the name of the inhibitor molecule, except for PDBID:2L8H (23), which shows the bound structure of arginine 4-methoxy-naphthylamide. The PDB indices for the other bound structures are as follows: ADP-1 (1ARJ (70)), Neomycin B (1QD3 (17)), KP-Z-41 (2KX5 (22)), L-22 (2KDQ (21)), RBT203 (1UUD (19)), Acetylpromazine (1LVJ (18)), RBT158 (1UUI (19)), RBT550 (1UTS (20)). Insets are shown that focus on the nodes that are closest to the bound structure, and the number below each shows the closest distance to the bound structure. The plots are sorted by the overall closest distance, and range from 23° for ADP-1 to 5.6° for Acetylpromazine. The insets are connected to transparent green circles in each network that show the area prior to magnification. Color figure is available online.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231733&req=5

Figure 6: Mapping ligand-bound structures on the TAR CSN. For each ligand-bound structure, we show a CSN for TAR with the node colorings indicating the distance in Euler angle space from each node to the ligand-bound structure. For NMR structures with multiple models, we plot the distance to the first model in the structure. Nodes that are greater than 50° are colored blue, and red nodes reveal structures that are close to the ligand-bound structure. Each plot is labeled by the name of the inhibitor molecule, except for PDBID:2L8H (23), which shows the bound structure of arginine 4-methoxy-naphthylamide. The PDB indices for the other bound structures are as follows: ADP-1 (1ARJ (70)), Neomycin B (1QD3 (17)), KP-Z-41 (2KX5 (22)), L-22 (2KDQ (21)), RBT203 (1UUD (19)), Acetylpromazine (1LVJ (18)), RBT158 (1UUI (19)), RBT550 (1UTS (20)). Insets are shown that focus on the nodes that are closest to the bound structure, and the number below each shows the closest distance to the bound structure. The plots are sorted by the overall closest distance, and range from 23° for ADP-1 to 5.6° for Acetylpromazine. The insets are connected to transparent green circles in each network that show the area prior to magnification. Color figure is available online.
Mentions: HIV-1 TAR RNA plays a critical role in the infectivity of HIV; after it is transcribed by RNA Pol II, it binds the viral Tat and host Cyclin T1 proteins that are vital for promoting efficient transcription of the downstream HIV genome (14–16). As such, much work has focused on developing inhibitors of the interaction between TAR and Tat (17–23,70). In Figure 6, we map a set of known structures of TAR with inhibitors bound. For the four bound complexes shown at the top of Figure 6, there only exist a few states that are close to the bound structure, and they are not significantly populated as determined by the sampling in WExplore. Although this might suggest a binding mechanism of induced fit, an alternative explanation is that these conformations are significantly populated in the dynamics of TAR, but are simply not populated here due to insufficient sampling. Consistent with our discussion above, these four complexes have near-coaxial interhelical conformations (βh = 3.8°, 7.2°, 3.0° and 7.5°, for ADP-1, Neomycin B, 2L8H and KP-Z-41, respectively). Note that we are using a Euler distance of 20° to define the smallest regions in WExplore, so a distance of greater than 20° can be considered to be not sampled by our ensemble.

Bottom Line: Our ensemble achieves similar agreement with experimental NMR data when compared with previous TAR computational studies, and is generated at a fraction of the computational cost.It clearly emerges from configuration space network analysis that the intermittent formation of the A22-U40 base pair acts as a reversible switch that enables sampling of interhelical conformations that would otherwise be topologically disallowed.We find that most previously determined ligand-bound structures are found in similar location in the network, and we use a sample-and-select approach to guide the construction of a set of novel conformations which can serve as the basis for future drug development efforts.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Michigan, 930 N University, Ann Arbor, MI 48109, USA.

Show MeSH