Conformational ensembles of an intrinsically disordered protein pKID with and without a KIX domain in explicit solvent investigated by all-atom multicanonical molecular dynamics

Koji Umezawa, Jinzen Ikebe, Mitsunori Takano, Haruki Nakamura, Junichi Higo

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The phosphorylated kinase-inducible activation domain (pKID) adopts a helix-loop-helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results.

Original languageEnglish
Pages (from-to)104-121
Number of pages18
JournalBiomolecules
Volume2
Issue number1
DOIs
Publication statusPublished - 2012 Mar

Keywords

  • Coupled folding and binding
  • Free energy landscape
  • IDP
  • Kinase-induced domain interacting domain
  • Mixed lineage leukemia (MLL)
  • Phosphorylated kinase inducible domain

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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