Atomistic simulations reveal structural disorder in the RAP74-FCP1 complex

Christopher Wostenberg, Sushant Kumar, William George Noid, Scott A. Showalter

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We report atomically detailed molecular dynamics simulations characterizing the interaction of the RAP74 winged helix domain with the intrinsically disordered C-terminal of FCP1. The RAP74 - FCP1 complex promotes the essential dephosphorylation of RNA polymerase II prior to initiation of transcription. Although disordered in solution, the C-terminal of FCP1 forms an amphipathic helix when bound to RAP74. Our simulations demonstrate that this interaction also reorganizes and stabilizes RAP74. These simulations illuminate the significance of hydrophobic contacts for stabilizing disordered protein complexes, provide new insight into the mechanism of protein binding by winged helix domains, and also reveal "dynamic fuzziness" in the complex as FCP1 retains significant flexibility after binding. In conjunction with our recent NMR experiments identifying residual structure in unbound FCP1, these simulations suggest that FCP1 loses relatively little conformational entropy upon binding and that the associated coupled folding - binding transition may be less sharp than expected.

Original languageEnglish (US)
Pages (from-to)13731-13739
Number of pages9
JournalJournal of Physical Chemistry B
Volume115
Issue number46
DOIs
StatePublished - Nov 24 2011

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RNA Polymerase II
Transcription
RNA
Molecular dynamics
Entropy
Nuclear magnetic resonance
disorders
helices
Proteins
Computer simulation
simulation
Experiments
proteins
folding
flexibility
interactions
entropy
molecular dynamics
nuclear magnetic resonance
Protein Binding

All Science Journal Classification (ASJC) codes

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

Cite this

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abstract = "We report atomically detailed molecular dynamics simulations characterizing the interaction of the RAP74 winged helix domain with the intrinsically disordered C-terminal of FCP1. The RAP74 - FCP1 complex promotes the essential dephosphorylation of RNA polymerase II prior to initiation of transcription. Although disordered in solution, the C-terminal of FCP1 forms an amphipathic helix when bound to RAP74. Our simulations demonstrate that this interaction also reorganizes and stabilizes RAP74. These simulations illuminate the significance of hydrophobic contacts for stabilizing disordered protein complexes, provide new insight into the mechanism of protein binding by winged helix domains, and also reveal {"}dynamic fuzziness{"} in the complex as FCP1 retains significant flexibility after binding. In conjunction with our recent NMR experiments identifying residual structure in unbound FCP1, these simulations suggest that FCP1 loses relatively little conformational entropy upon binding and that the associated coupled folding - binding transition may be less sharp than expected.",
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Atomistic simulations reveal structural disorder in the RAP74-FCP1 complex. / Wostenberg, Christopher; Kumar, Sushant; Noid, William George; Showalter, Scott A.

In: Journal of Physical Chemistry B, Vol. 115, No. 46, 24.11.2011, p. 13731-13739.

Research output: Contribution to journalArticle

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