Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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. While G-quartet stems have been well characterised, 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.
Original languageEnglish
Pages (from-to)2723
Number of pages2735
JournalNucleic Acids Research
Volume41
Issue number4
DOIs
Publication statusPublished - 01 Feb 2013

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G-Quadruplexes
Crowding
Sugar Phosphates
Ligands
Molecular Dynamics Simulation
Base Pairing
Rationalization

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Islam, B., Sgobba, M., Laughton, C., Orozco, M., Sponer, J., Neidle, S., ... Shozeb Haider (2013). Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale. Nucleic Acids Research, 41(4), 2723. https://doi.org/10.1093/nar/gks1331
Islam, Barira ; Sgobba, Miriam ; Laughton, Charles ; Orozco, Modesto ; Sponer, Jiri ; Neidle, Stephen ; Haider, Shozeb ; Shozeb Haider. / Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale. In: Nucleic Acids Research. 2013 ; Vol. 41, No. 4. pp. 2723.
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Islam, B, Sgobba, M, Laughton, C, Orozco, M, Sponer, J, Neidle, S, Haider, S & Shozeb Haider 2013, 'Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale', Nucleic Acids Research, vol. 41, no. 4, pp. 2723. https://doi.org/10.1093/nar/gks1331

Conformational Dynamics of the Human Propeller Telomeric DNA Quadruplex on a Microsecond Time Scale. / Islam, Barira; Sgobba, Miriam; Laughton, Charles; Orozco, Modesto; Sponer, Jiri; Neidle, Stephen; Haider, Shozeb; Shozeb Haider.

In: Nucleic Acids Research, Vol. 41, No. 4, 01.02.2013, p. 2723.

Research output: Contribution to journalArticle

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