Keywords

Conformational Selection, Induced Fit, Protein Dynamics, Allostery, Noise, Binding Mechanisms

Reference

DOI: 10.1016/j.tibs.2010.04.009

Abstract

Recent single-molecule and NMR studies reveal binding mechanisms far more dynamic and complex than previously appreciated.
This review proposes an extended conformational selection model, where binding is not merely conformational selection or induced fit, but a spectrum of selection and adjustment processes.
Induced fit becomes a subset of this dynamic repertoire, influenced by bond types, protein flexibility, and partner differences.
Importantly, independent dynamic segments (discrete breathers) within proteins guide conformational transitions and allosteric communication, potentially sensitive to mutations.
The review further explores how crowding, folding/unfolding, and “NOISE!?” contribute to binding, signaling, and aggregation in the cellular environment.

Notes

1. Foundations of Protein Binding Models

  • Lock-and-Key: Fixed shape, perfect fit.
  • Induced Fit: Conformational change after initial contact.
  • Conformational Selection: Protein samples multiple conformations, and ligand binds to a pre-existing competent state.
  • Extended Conformational Selection: Blend of selection and adjustment, dynamic energy landscape shifting upon encounter, mutual adaptation.

Key idea: No one-size-fits-all — proteins may use different models simultaneously, even within different segments of the same molecule!

2. Game Theory Perspective on Binding

  • Proteins act as “players”:
    • Rigid (“hawks”) vs. flexible (“doves”).
  • Binding is a negotiation on an energy landscape, influenced by partner dynamics and interaction strength.
  • Interaction type dictates binding path: weak/strong, flexible/rigid combinations shape the dynamic binding route.

3. Role of Independent Dynamic Segments (Discrete Breathers)

  • Specific protein segments with localized, independent motions.
  • Crucial for initiating and propagating conformational changes, especially in allosteric regulation.
  • Often near binding or catalytic sites, they transmit energy, enabling conformational shifts upon ligand binding.
  • Sensitive to mutation, potentially altering signaling pathways or catalytic activity.

4. Mediators and Environmental Factors

  • Chaperones and water molecules help mediate binding by reducing conflicts and stabilizing intermediates.
  • Molecular crowding in cells enhances conformational selection, increasing contact frequency.
  • Folding and unfolding (notably for IDPs) is integral to binding, enabling multistage engagement.

5. Conformational Noise and Signaling

  • Dynamic fluctuations (noise) within protein ensembles enable stochastic transitions between conformational states.
  • Stochastic resonance: Random “noise” helps weak signals surpass activation thresholds — amplifying signaling.

🌈 NOISE!? YES — conformational fluctuations that boost signal strength and fidelity, helping proteins “hear” weak signals! 🌈

  • Noise in conformational dynamics ensures sensitive, tunable responses, crucial for cellular signaling precision.

6. Integration of Mechanisms — Duality of Binding

  • Proteins use both conformational selection and induced fit — not mutually exclusive but complementary steps:
    • Selection of a pre-existing state, followed by fine-tuning (adjustments) for high affinity and specificity.
  • Different regions of a protein might follow different mechanisms — multi-layered strategy for efficient recognition and response.

7. Contextual Modulators of Binding Pathways

  • Temperature: Increases flexibility, favoring conformational selection.
  • Protein concentration and crowding: Promote encounters, shifting balance toward selection.
  • Chaperones: Bias partners towards induced fit.
  • Post-translational modifications (e.g., phosphorylation): Stabilize active conformations, altering binding preferences.

8. RD’s Takeaways and Inspiration

  • Binding is NOT static — it’s multi-pathway, flexible, and highly context-dependent.
  • Extended conformational selection model perfectly fits dynamic systems like IDPs and multi-partner signaling hubs.
  • Independent dynamic segments as information conduits for allostery = a fascinating concept for mutational analysis!
  • NOISE as a biological amplifier — potential tie-in for RD’s work on signaling fidelity and threshold responses.
  • Possible application to drug design: Targeting dynamic regions rather than static pockets — “hitting the moving parts.”

Take-home Messages

  • Protein-ligand binding is dynamic, involving conformational selection, induced fit, and independent dynamic segments.
  • NOISE!? — Conformational fluctuations amplify signals, critical for sensitive biological responses.
  • Binding models are context- and region-dependent, influenced by partner dynamics, cellular environment, and post-translational modifications.
  • Independent dynamic segments serve as control hubs for allosteric regulation, mutational targets, and energy flow.
  • The extended conformational selection model is a comprehensive framework, unifying diverse binding phenomena and explaining protein adaptability in complex cellular environments.