Abstract
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 multipathway 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.
| Original language | English |
|---|---|
| Pages (from-to) | 8673-8693 |
| Number of pages | 21 |
| Journal | Nucleic Acids Research |
| Volume | 43 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 1 Oct 2015 |
| Externally published | Yes |
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Extended molecular dynamics of a c-kit promoter quadruplex. / Islam, Barira; Stadlbauer, Petr; Krepl, Miroslav; Koca, Jaroslav; Neidle, Stephen; Haider, Shozeb; Sponer, Jiri.
In: Nucleic Acids Research, Vol. 43, No. 18, 01.10.2015, p. 8673-8693.Research output: Contribution to journal › Article
TY - JOUR
T1 - Extended molecular dynamics of a c-kit promoter quadruplex
AU - Islam, Barira
AU - Stadlbauer, Petr
AU - Krepl, Miroslav
AU - Koca, Jaroslav
AU - Neidle, Stephen
AU - Haider, Shozeb
AU - Sponer, Jiri
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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 multipathway 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.
AB - 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 multipathway 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.
UR - http://www.scopus.com/inward/record.url?scp=84949933642&partnerID=8YFLogxK
U2 - 10.1093/nar/gkv785
DO - 10.1093/nar/gkv785
M3 - Article
VL - 43
SP - 8673
EP - 8693
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 18
ER -