Biomolecules 2012, 2(1), 104-121; doi:10.3390/biom2010104
Article

Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics

1 Graduate School of Advanced Science and Engineering, Waseda University, Okubo 3-4-1, Shinjuku-Ku, Tokyo 169-8555, Japan 2 Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan
* Author to whom correspondence should be addressed.
Received: 28 December 2011; in revised form: 11 February 2012 / Accepted: 12 February 2012 / Published: 22 February 2012
(This article belongs to the Special Issue Feature Papers)
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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.
Keywords: IDP; phosphorylated kinase inducible domain; kinase-induced domain interacting domain; coupled folding and binding; free energy landscape; mixed lineage leukemia (MLL)

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MDPI and ACS Style

Umezawa, K.; Ikebe, J.; Takano, M.; Nakamura, H.; Higo, J. Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics. Biomolecules 2012, 2, 104-121.

AMA Style

Umezawa K, Ikebe J, Takano M, Nakamura H, Higo J. Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics. Biomolecules. 2012; 2(1):104-121.

Chicago/Turabian Style

Umezawa, Koji; Ikebe, Jinzen; Takano, Mitsunori; Nakamura, Haruki; Higo, Junichi. 2012. "Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics." Biomolecules 2, no. 1: 104-121.

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