Journal Article

Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale

Barira Islam, Miriam Sgobba, Charlie Laughton, Modesto Orozco, Jiri Sponer, Stephen Neidle and Shozeb Haider

in Nucleic Acids Research

Volume 41, issue 4, pages 2723-2735
Published in print February 2013 | ISSN: 0305-1048
Published online January 2013 | e-ISSN: 1362-4962 | DOI: https://dx.doi.org/10.1093/nar/gks1331

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The human telomeric DNA sequence with four repeats can fold into a parallel-stranded propeller-type topology. NMR structures solved under molecular crowding experiments correlate with the crystal structures found with crystal-packing interactions that are effectively equivalent to molecular crowding. This topology has been used for rationalization of ligand design and occurs experimentally in a number of complexes with a diversity of ligands, at least in the crystalline state. Although G-quartet stems have been well characterized, the interactions of the TTA loop with the G-quartets are much less defined. To better understand the conformational variability and structural dynamics of the propeller-type topology, we performed molecular dynamics simulations in explicit solvent up to 1.5 μs. The analysis provides a detailed atomistic account of the dynamic nature of the TTA loops highlighting their interactions with the G-quartets including formation of an A:A base pair, triad, pentad and hexad. The results present a threshold in quadruplex simulations, with regards to understanding the flexible nature of the sugar-phosphate backbone in formation of unusual architecture within the topology. Furthermore, this study stresses the importance of simulation time in sampling conformational space for this topology.

Journal Article.  7423 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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