The Perturbed Free-Energy Landscape: Linking Ligand Binding to Biomolecular Folding

Area of Science:

• Biophysics
• Structural Biology
• Computational Chemistry

Background:

• Ligand binding's impact on biomolecular conformation is vital for drug design, enzyme function, and gene regulation.
• Common models like "lock and key" and "induced fit" describe these interactions.
• The linked equilibria model suggests ligand binding perturbs the free-energy landscape (FEL).

Purpose of the Study:

• To present a unified, quantitative theory of ligand-induced conformational change based on the perturbed FEL concept.
• To introduce the "binding affinity landscape" (BAL) as a map of binding free energy across conformational space.
• To demonstrate how the BAL unifies and explains existing descriptive models of ligand-receptor interactions.

Main Methods:

• Developing a quantitative theory of ligand-induced conformational change by extending the FEL concept.
• Mapping binding free energy onto biomolecular conformational space to create the BAL.
• Reviewing experimental and computational studies, with a focus on RNA, to exemplify the perturbed FEL.

Main Results:

• The perturbed FEL framework quantitatively explains ligand-induced conformational changes.
• The BAL provides a unified view, reconciling "lock and key", "induced fit", and "conformation selection" models.
• Recent studies on RNA demonstrate the applicability of the perturbed FEL theory.

Conclusions:

• The perturbed FEL and BAL offer a powerful, unified framework for understanding ligand-induced biomolecular dynamics.
• This approach provides new insights for designing ligands and advancing structural and systems biology.
• It motivates novel experimental and theoretical methodologies in molecular interactions.