TY - JOUR
T1 - Free energy landscapes of RNA/RNA complexes
T2 - With applications to snRNA complexes in spliceosomes
AU - Cao, Song
AU - Chen, Shi Jie
N1 - Funding Information:
We thank Drs Kathleen Hall, Brenda Peculis and Jonathan Staley for valuable discussions. Funding for this project was provided by NIH (GM063732, to S.-J.C.) and MU life science fellowship (to S.C.).
PY - 2006/3/17
Y1 - 2006/3/17
N2 - We develop a statistical mechanical model for RNA/RNA complexes with both intramolecular and intermolecular interactions. As an application of the model, we compute the free energy landscapes, which give the full distribution for all the possible conformations, for U4/U6 and U2/U6 in major spliceosome and U4atac/U6atac and U12/U6atac in minor spliceosome. Different snRNA experiments found contrasting structures, our free energy landscape theory shows why these structures emerge and how they compete with each other. For yeast U2/U6, the model predicts that the two distinct experimental structures, the four-helix junction structure and the helix Ib-containing structure, can actually coexist and specifically compete with each other. In addition, the energy landscapes suggest possible mechanisms for the conformational switches in splicing. For instance, our calculation shows that coaxial stacking is essential for stabilizing the four-helix junction in yeast U2/U6. Therefore, inhibition of the coaxial stacking possibly by protein-binding may activate the conformational switch from the four-helix junction to the helix Ib-containing structure. Moreover, the change of the energy landscape shape gives information about the conformational changes. We find multiple (native-like and misfolded) intermediates formed through base-pairing rearrangements in snRNA complexes. For example, the unfolding of the U2/U6 undergoes a transition to a misfolded state which is functional, while in the unfolding of U12/U6atac, the functional helix Ib is found to be the last one to unfold and is thus the most stable structural component. Furthermore, the energy landscape gives the stabilities of all the possible (functional) intermediates and such information is directly related to splicing efficiency.
AB - We develop a statistical mechanical model for RNA/RNA complexes with both intramolecular and intermolecular interactions. As an application of the model, we compute the free energy landscapes, which give the full distribution for all the possible conformations, for U4/U6 and U2/U6 in major spliceosome and U4atac/U6atac and U12/U6atac in minor spliceosome. Different snRNA experiments found contrasting structures, our free energy landscape theory shows why these structures emerge and how they compete with each other. For yeast U2/U6, the model predicts that the two distinct experimental structures, the four-helix junction structure and the helix Ib-containing structure, can actually coexist and specifically compete with each other. In addition, the energy landscapes suggest possible mechanisms for the conformational switches in splicing. For instance, our calculation shows that coaxial stacking is essential for stabilizing the four-helix junction in yeast U2/U6. Therefore, inhibition of the coaxial stacking possibly by protein-binding may activate the conformational switch from the four-helix junction to the helix Ib-containing structure. Moreover, the change of the energy landscape shape gives information about the conformational changes. We find multiple (native-like and misfolded) intermediates formed through base-pairing rearrangements in snRNA complexes. For example, the unfolding of the U2/U6 undergoes a transition to a misfolded state which is functional, while in the unfolding of U12/U6atac, the functional helix Ib is found to be the last one to unfold and is thus the most stable structural component. Furthermore, the energy landscape gives the stabilities of all the possible (functional) intermediates and such information is directly related to splicing efficiency.
KW - Folding pathways
KW - Free energy landscape
KW - Major and minor spliceosomes
KW - Misfolded state
KW - RNA/RNA complex
UR - http://www.scopus.com/inward/record.url?scp=33644779957&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2005.12.014
DO - 10.1016/j.jmb.2005.12.014
M3 - Article
C2 - 16413034
AN - SCOPUS:33644779957
VL - 357
SP - 292
EP - 312
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 1
ER -