posted on 2014-06-10, 00:00authored byMateusz Kurcinski, Andrzej Kolinski, Sebastian Kmiecik
A complex of the phosphorylated kinase-inducible
domain (pKID)
with its interacting domain (KIX) is a model system for studies of
mechanisms by which intrinsically unfolded proteins perform their
functions. These mechanisms are not fully understood. Using an efficient
coarse-grained model, ab initio simulations were performed of the
coupled folding and binding of the pKID to the KIX. The simulations
start from an unbound, randomly positioned and disordered pKID structure.
During the simulations the pKID chain and its position remain completely
unrestricted, while the KIX backbone is limited to near-native fluctuations.
Ab initio simulations of such large-scale conformational transitions,
unaffected by any knowledge about the bound pKID structure, remain
inaccessible to classical simulations. Our simulations recover an
ensemble of transient encounter complexes in good agreement with experimental
results. We find that a key folding and binding step is linked to
the formation of weak native interactions between a preformed nativelike
fragment of a pKID helix and KIX surface. Once that nucleus forms,
the pKID chain may condense from a largely disordered encounter ensemble
to a natively bound and ordered conformation. The observed mechanism
is reminiscent of a nucleation–condensation model, a common
scenario for folding of globular proteins.