Extended molecular dynamics of a c-kit promoter quadruplex

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Authors

ISLAM Barira STADLBAUER Petr KREPL Miroslav KOČA Jaroslav NEIDLE Stephen HAIDER Shozeb ŠPONER Jiří

Year of publication 2015
Type Article in Periodical
Magazine / Source Nucleic Acids Research
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://nar.oxfordjournals.org/content/43/18/8673.full.pdf+html
Doi http://dx.doi.org/10.1093/nar/gkv785
Field Biochemistry
Keywords TELOMERIC G-QUADRUPLEX; INTRAMOLECULAR DNA QUADRUPLEXES; GASTROINTESTINAL STROMAL TUMOR; PARALLEL G-QUADRUPLEXES; PARTICLE MESH EWALD; AMBER FORCE-FIELD; G-TRACT LENGTH; RNA LOOP-E; NUCLEIC-ACIDS; ION-BINDING
Attached files
Description 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. 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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