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. 2014 Jun 10;10(6):2224-31.
doi: 10.1021/ct500287c.

Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations

Mateusz Kurcinski  1 , Andrzej Kolinski  1 , Sebastian Kmiecik  1
Affiliations

Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations

Mateusz Kurcinski et al. J Chem Theory Comput. .

Abstract

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.

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