The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations

Tomoka Furukawa-Hagiya, Tadaomi Furuta, Shuntaro Chiba, Yoshiro Sohma, Minoru Sakurai

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel belonging to the ATP binding cassette (ABC) protein superfamily. Currently, it remains unclear how ATP binding causes the opening of the channel gate at the molecular level. To clarify this mechanism, we first constructed an atomic model of the inward-facing CFTR using the X-ray structures of other ABC proteins. Molecular dynamics (MD) simulations were then performed to explore the structure and dynamics of the inward-facing CFTR in a membrane environment. In the MgATP-bound state, two nucleotide-binding domains (NBDs) formed a head-to-tail type of dimer, in which the ATP molecules were sandwiched between the Walker A and signature motifs. Alternatively, one of the final MD structures in the apo state was similar to that of a "closed-apo" conformation found in the X-ray analysis of ATP-free MsbA. Principal component analysis for the MD trajectory indicated that NBD dimerization causes significant structural and dynamical changes in the transmembrane domains (TMDs), which is likely indicative of the formation of a chloride ion access path. This study suggests that the free energy gain from ATP binding acts as a driving force not only for NBD dimerization but also for NBD-TMD concerted motions.

Original languageEnglish
Pages (from-to)83-93
Number of pages11
JournalJournal of Physical Chemistry B
Volume117
Issue number1
DOIs
Publication statusPublished - 2013 Jan 10

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cystic fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
adenosine triphosphate
Adenosinetriphosphate
regulators
strokes
Molecular dynamics
Adenosine Triphosphate
molecular dynamics
Nucleotides
nucleotides
Computer simulation
Facings
Dimerization
simulation
dimerization
Proteins
chlorides
X ray analysis
Chloride Channels

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films

Cite this

The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations. / Furukawa-Hagiya, Tomoka; Furuta, Tadaomi; Chiba, Shuntaro; Sohma, Yoshiro; Sakurai, Minoru.

In: Journal of Physical Chemistry B, Vol. 117, No. 1, 10.01.2013, p. 83-93.

Research output: Contribution to journalArticle

Furukawa-Hagiya, Tomoka ; Furuta, Tadaomi ; Chiba, Shuntaro ; Sohma, Yoshiro ; Sakurai, Minoru. / The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations. In: Journal of Physical Chemistry B. 2013 ; Vol. 117, No. 1. pp. 83-93.
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