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Extended molecular dynamics of a c-kit promoter quadruplex

B. Islam, P. Stadlbauer, M. Krepl, J. Koca, S. Neidle, S. Haider, J. Sponer,

. 2015 ; 43 (18) : 8673-93. [pub] 20150805

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc16020441

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 μs long, ∼50 μs 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 μs-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. The stability gain by forming the internal network of GA base pairs and stacks of this loop may be dictating which of the many possible quadruplex topologies is observed in the ground state by this promoter quadruplex.

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$a Islam, Barira $u Central European Institute of Technology (CEITEC), Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic.
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$a 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 μs long, ∼50 μs 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 μs-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. The stability gain by forming the internal network of GA base pairs and stacks of this loop may be dictating which of the many possible quadruplex topologies is observed in the ground state by this promoter quadruplex.
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$a Stadlbauer, Petr $u Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic.
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$a Krepl, Miroslav $u Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic.
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$a Koca, Jaroslav $u Central European Institute of Technology (CEITEC), Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic National Center for Biomolecular Research, Faculty of Science, Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic.
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$a Neidle, Stephen $u UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK s.neidle@ucl.ac.uk.
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$a Haider, Shozeb $u UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK shozeb.haider@ucl.ac.uk.
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$a Sponer, Jiri $u Central European Institute of Technology (CEITEC), Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic sponer@ncbr.muni.cz.
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