Keywords

IDP, Fly-casting, Fuzzy Complex, Conformational Selection, Induced Fit, Promiscuous Interactions, NMR, Kinetics

Reference

DOI: 10.3389/fmolb.2016.00052

💫 Amazing Review, Super Knowledged for IDP! 💫

🌟 Absolutely essential reading for anyone working on IDPs, binding mechanisms, and signaling! 🌟

Abstract

Intrinsically disordered proteins (IDPs) challenge the classical structure-function paradigm by functioning without a stable 3D structure.
They bind partners via diverse mechanisms, often folding upon binding, but also retaining flexibility in “fuzzy complexes.”
This review explores multiple models of IDP interactions, including conformational selection, induced fit, and fly-casting, integrating insights from NMR, transient kinetics, and molecular simulations.
The emerging picture is system-dependent, showing no universal mechanism but a continuum of binding modes adapted to specific cellular functions.

Notes

1. General Concepts and Preknowledge

  • IDPs play critical roles in signaling, transcription, and regulation, often interacting transiently and promiscuously.
  • Binding without strong affinity but high specificity is key to fast, reversible interactions — essential for cellular signaling fidelity.
  • IDP binding mechanisms can include:
    • Conformational selection: Pre-formed states in the ensemble bind directly.
    • Induced fit: Folding occurs upon binding.
    • Fly-casting: Binding initiated while unstructured, capturing partners from a distance.
    • Fuzzy complexes: Retaining flexibility and multiple interaction modes even when bound.

2. Experimental and Computational Methods

  • Transient Kinetics: Rapid mixing and perturbation to track binding rates and mechanisms.
  • NMR Spectroscopy: Residue-level observation of chemical shift changes during binding to resolve kinetics and exchange regimes.
  • Molecular Simulations: MD, REMD, metadynamics visualize binding/folding at atomic resolution.

3. Fly-Casting Mechanism

  • Disordered proteins extend their capture radius, potentially accelerating association rates.
  • Debated mechanism: While IDPs often bind near diffusion limits, pre-structured elements can also enhance capture.
  • Fly-casting may work in combination with other mechanisms, speeding up initial contact, followed by induced folding.

4. Conformational Selection vs. Induced Fit

  • Conformational selection: Pre-existing binding-competent conformations within the disordered ensemble.
  • Induced fit: Folding driven by binding interface formation.
  • Most IDP interactions are combinations of both, involving initial recognition by pre-formed elements, followed by further folding and adjustment.
  • This combined mechanism enables flexible but specific interactions, crucial for signaling functions.

5. Fuzzy Complexes and Functional Implications

  • Fuzzy complexes: Bound states retaining significant flexibility, enabling multisite interactions and dynamic binding.
  • Such dynamic complexes allow IDPs to interact with multiple partners, adjusting to context-dependent signaling needs.
  • Functional advantages:
    • Promiscuity: One IDP can engage various targets.
    • Versatility: Multiple conformational states = multiple binding modes.
    • Dynamic regulation: Fast binding/unbinding crucial for transient signaling.

6. Affinity, Specificity, and Thermodynamics

  • High specificity without high affinity: Essential for transient signaling events.
  • Enthalpy-entropy compensation:
    • Entropy loss from folding upon binding offset by favorable enthalpic contacts (hydrophobic, electrostatic).
  • Proline mutations: Disrupt IDP binding by interfering with hydrogen bonding and introducing cis-trans isomerization complications.

7. RD’s Thoughts and Takeaways

  • Incredible resource for understanding IDP interactions — beyond simple “folds on binding” models.
  • The integration of conformational selection and induced fit aligns with RD’s own conceptualization of regulated disorder.
  • Fly-casting as a potential rate-enhancing feature, but with caveats and limitations, is important for RD’s modeling efforts.
  • Fuzzy complexes inspire new thinking about multivalent, dynamic interfaces — relevant for RD’s interest in multi-target protein interactions.
  • Thermodynamic balancing explains why IDPs bind weakly but specifically, a principle to consider in drug design targeting IDPs.

Take-home Messages

  • IDPs utilize a blend of conformational selection, induced fit, and fly-casting, depending on context and partner.
  • Fuzzy complexes are hallmark IDP interactions — dynamic, versatile, and functionally adaptable.
  • Affinity and specificity are decoupled: IDPs achieve functional precision without permanent binding, enabling fine-tuned signaling.
  • Proline-directed complications highlight the need to consider sequence effects on IDP dynamics.
  • 🌟 Amazing review for anyone working on IDP dynamics, signaling, and interaction mechanisms! 🌟