title: Binding of two intrinsically disordered peptides to a multi-specific protein: a combined Monte Carlo and molecular dynamics study.
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 [Formula: see text]-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.
authors.affiliation: Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics group, Lund University, Lund, Sweden.
authors.forename: Iskra
authors.initials: I
authors.lastname: Staneva
authors.forename: Yongqi
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Liu
authors.forename: Stefan
authors.initials: S
authors.lastname: Wallin
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D051347:CapZ Actin Capping Protein; D003198:Computer Simulation; D008956:Models, Chemical; D015233:Models, Statistical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000648:ultrastructure*; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments; D011485:Protein Binding; D011487:Protein Conformation; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D051347:CapZ Actin Capping Protein; D009414:Nerve Growth Factors; D009842:Oligopeptides; D010446:Peptide Fragments; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C475482:TRTK-12 peptide; D016159:Tumor Suppressor Protein p53