Nucleic Acids Research Advance Access originally published online on April 15, 2009
Nucleic Acids Research 2009 37(11):3670-3679; doi:10.1093/nar/gkp156
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Nucleic Acids Research, 2009, Vol. 37, No. 11 3670-3679
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Constructing RNA dynamical ensembles by combining MD and motionally decoupled NMR RDCs: new insights into RNA dynamics and adaptive ligand recognition
1Department of Chemistry, University of California Irvine, 1102 Natural Sciences 2, Irvine, CA 92697 and 2Department of Chemistry & Biophysics, The University of Michigan, Ann Arbor, MI 48109, USA
*To whom correspondence should be addressed. Tel/Fax: +734 647 4865; Email: hashimi{at}umich.edu Correspondence may also be addressed to Ioan Andricioaei. Tel: +949 824 3569; Fax: +949 824 9920; Email: andricio{at}uci.edu
Received December 3, 2008. Revised February 23, 2009. Accepted February 24, 2009.
We describe a strategy for constructing atomic resolution dynamical ensembles of RNA molecules, spanning up to millisecond timescales, that combines molecular dynamics (MD) simulations with NMR residual dipolar couplings (RDC) measured in elongated RNA. The ensembles are generated via a Monte Carlo procedure by selecting snap-shot from an MD trajectory that reproduce experimentally measured RDCs. Using this approach, we construct ensembles for two variants of the transactivation response element (TAR) containing three (HIV-1) and two (HIV-2) nucleotide bulges. The HIV-1 TAR ensemble reveals significant mobility in bulge residues C24 and U25 and to a lesser extent U23 and neighboring helical residue A22 that give rise to large amplitude spatially correlated twisting and bending helical motions. Omission of bulge residue C24 in HIV-2 TAR leads to a significant reduction in both the local mobility in and around the bulge and amplitude of inter-helical bending motions. In contrast, twisting motions of the helices remain comparable in amplitude to HIV-1 TAR and spatial correlations between them increase significantly. Comparison of the HIV-1 TAR dynamical ensemble and ligand bound TAR conformations reveals that several features of the binding pocket and global conformation are dynamically preformed, providing support for adaptive recognition via a ‘conformational selection’ type mechanism.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First authors.
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