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, α
A and
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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, α
A and α
B. 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, α
A and α
B exhibited a nascent helix propensity; the propensity of α
A was stronger than that of α
B, which agrees with experimental results. In the bound state, the free-energy landscape of α
B involved two low free-energy fractions: native-like and non-native fractions. This result suggests that α
B folds according to the induced-fit mechanism. The α
B-helix direction was well aligned as in the NMR complex structure, although the α
A helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the α
B 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.
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