Abstract
The unique ability of intrinsically disordered proteins (IDPs) to fold upon binding to partner molecules makes them functionally well-suited for cellular communication networks. For example, the folding-binding of different IDP sequences onto the same surface of an ordered protein provides a mechanism for signaling in a many-to-one manner. Here, we study the molecular details of this signaling mechanism by applying both Molecular Dynamics and Monte Carlo methods to S100B, a calcium-modulated homodimeric protein, and two of its IDP targets, p53 and TRTK-12. Despite adopting somewhat different conformations in complex with S100B and showing no apparent sequence similarity, the two IDP targets associate in virtually the same manner. As free chains, both target sequences remain flexible and sample their respective bound, natively -helical states to a small extent. Association occurs through an intermediate state in the periphery of the S100B binding pocket, stabilized by nonnative interactions which are either hydrophobic or electrostatic in nature. Our results highlight the importance of overall physical properties of IDP segments, such as net charge or presence of strongly hydrophobic amino acids, for molecular recognition via coupled folding-binding.
Highlights
It has become clear that many functional proteins do not fold into unique three-dimensional structures, as expected from the classical view of proteins, but remain highly conformationally dynamic under native conditions
The peptides assume different structures in the bound state, there are similarities in how they associate with S100B
Summary and Conclusion We have used a combination of Molecular Dynamics (MD) and MC all-atom simulations to understand the coupled folding and binding of two disordered peptides, p53 and TRTK-12, to the Ca2z-loaded form of S100B, as an example of a many-to-one signaling mechanism
Summary
It has become clear that many functional proteins do not fold into unique three-dimensional structures, as expected from the classical view of proteins, but remain highly conformationally dynamic under native conditions. We cannot directly assess kinetic aspects of the binding process with our MC approach, we can examine the structural characteristics of peptide conformations which are neither entirely bound nor in the unbound state As shown above, both sequences exhibit similar plateau-like regions in the Nc free energy profiles (see Figure 3). We note that preliminary simulations for the interaction between S100B and NDR, performed using our all-atom MC approach, produced a minimum-energy conformation where the (sole) aromatic residue of the NDR peptide is involved in binding in a similar way as for p53 and TRTK-12 (see Figure S3). To a small extent do they sample their respective S100B-bound structures Both p53 and TRTK-12 populate an intermediate, metastable state during the folding-binding process, which may serve as an initial encounter complex of the interaction. Major disparities between the two S100B targets become apparent only in the final bound state, where the patterns of contacts with the S100B surface are significantly dissimilar
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