Contribution of Proline to the Pre-structuring Tendency of Transient Helical Secondary Structure Elements in Intrinsically Disordered Proteins

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Intrinsically Disordered Protein (IDP), PreSMo (Pre-Structured Motif), Flanking Proline, Molecular Dynamics Simulation.

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Background: IDPs function without relying on three-dimensional structures. No clear rationale for such a behavior is available yet. PreSMos are transient secondary structures observed in the target-free IDPs and serve as the target-binding "active" motifs in IDPs. Prolines are frequently found in the flanking regions of PreSMos. Contribution of prolines to the conformational stability of the helical PreSMos in IDPs is investigated.

Methods: MD simulations are performed for several IDP segments containing a helical PreSMo and the flanking prolines. To measure the influence of flanking-prolines on the structural content of a helical PreSMo calculations were done for wild type as well as for mutant segments with Pro→Asp, His, Lys, or Ala. The change in the helicity due to removal of a proline was measured both for the PreSMo region and for the flanking regions.

Results: The α-helical content in ~70% of the helical PreSMos at the early stage of simulation decreases due to replacement of an N-terminal flanking proline by other residues whereas the helix content in nearly all PreSMos increases when the same replacements occur at the C-terminal flanking region. The helix destabilizing/terminating role of the C-terminal flanking prolines is more pronounced than the helix promoting effect of the N-terminal flanking prolines.

General significance: This work represents a novel example demonstrating that a proline is encoded in an IDP with a defined purpose. The helical PreSMos presage their target-bound conformations. As they most likely mediate IDP-target binding via conformational selection their helical content can be an important feature for IDP function.

Keywords: Flanking proline; Intrinsically disordered protein (IDP); Molecular dynamics simulation; PreSMo (Pre-Structured Motif).

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Citation / Publisher Attribution

Biochimica et Biophysica Acta (BBA) - General Subjects, v. 1840, issue 3, p. 993-1003