Extended molecular dynamics of a c-kit promoter quadruplex

0455886 - BFÚ 2016 RIV GB eng J - Journal Article
Islam, B. - Stadlbauer, Petr - Krepl, Miroslav - Koča, J. - Neidle, S. - Haider, S. - Šponer, Jiří
Extended molecular dynamics of a c-kit promoter quadruplex.
Nucleic Acids Research. Roč. 43, č. 18 (2015), s. 8673-8693. ISSN 0305-1048. E-ISSN 1362-4962
R&D Projects: GA ČR(CZ) GAP208/11/1822
Institutional support: RVO:68081707
Keywords : TELOMERIC G-QUADRUPLEX * INTRAMOLECULAR DNA QUADRUPLEXES * GASTROINTESTINAL STROMAL TUMOR
Subject RIV: BO - Biophysics
Impact factor: 9.202, year: 2015

The 22-mer c-kit promoter sequence folds into a parallel-stranded quadruplex with a unique structure, which has been elucidated by crystallographic and NMR methods and shows a high degree of structural conservation. We have carried out a series of extended (up to 10 mu s long, similar to 50 mu s in total) molecular dynamics simulations to explore conformational stability and loop dynamics of this quadruplex. Unfolding no-salt simulations are consistent with a multi-pathway model of quadruplex folding and identify the single-nucleotide propeller loops as the most fragile part of the quadruplex. Thus, formation of propeller loops represents a peculiar atomistic aspect of quadruplex folding. Unbiased simulations reveal mu s-scale transitions in the loops, which emphasizes the need for extended simulations in studies of quadruplex loops. We identify ion binding in the loops which may contribute to quadruplex stability. The long lateral-propeller loop is internally very stable but extensively fluctuates as a rigid entity. It creates a size-adaptable cleft between the loop and the stem, which can facilitate ligand binding.
Permanent Link: http://hdl.handle.net/11104/0256495