Intrinsic disorder accelerates dissociation rather than association.
The intrinsically disordered protein (IDP) has distinct properties both physically and biologically: it often becomes folded when binding to the target and is frequently involved in signal transduction. The physical property seems to be compatible with the biological property where fast association and dissociation between IDP and the target are required. While fast association has been well studied, fueled by the fly-casting mechanism, the dissociation kinetics has received less attention. We here study how the intrinsic disorder affects the dissociation kinetics, as well as the association kinetics, paying attention to the interaction strength at the binding site (i.e., the quality of the "fly lure"). Coarse-grained molecular dynamics simulation of the pKID-KIX system, a well-studied IDP system, shows that the association rate becomes larger as the disorder-inducing flexibility that was imparted to the model is increased, but the acceleration is marginal and turns into deceleration as the quality of the fly lure is worsened. In contrast, the dissociation rate is greatly enhanced as the disorder is increased, indicating that intrinsic disorder serves for rapid signal switching more effectively through dissociation than association. Proteins 2016; 84:1124-1133. © 2016 Wiley Periodicals, Inc.
Department of Pure and Applied Physics, Waseda University, Okubo 3-4-1, Shinjuku-Ku, Tokyo, 169-8555, Japan.
Koji
K
Umezawa
Department of Pure and Applied Physics, Waseda University, Okubo 3-4-1, Shinjuku-Ku, Tokyo, 169-8555, Japan.
Jun
J
Ohnuki
Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
Junichi
J
Higo
Department of Pure and Applied Physics, Waseda University, Okubo 3-4-1, Shinjuku-Ku, Tokyo, 169-8555, Japan.
Mitsunori
M
Takano
D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry*; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D013816:Thermodynamics
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D064267:Intrinsically Disordered Proteins
Langevin dynamics; capture radius; coarse-grained model; coupled folding and binding; flexibility; fly-casting mechanism; molecular dynamics simulation; phosphorylation; signaling