Elucidating the energetic contributions to the binding free energy

Area of Science:

• Computational chemistry
• Biophysics
• Molecular dynamics

Background:

• Understanding ligand-receptor binding free energy (ΔG⁰) is crucial in drug discovery.
• Existing methods often involve approximations or extensive simulations.
• A precise theoretical framework is needed to dissect the energetic contributions to binding.

Purpose of the Study:

• To derive exact equations for the components of binding free energy (ΔG⁰).
• To introduce and apply the perturbation-divergence formalism (PDF) for analyzing ligand-receptor interactions.
• To provide a new perspective on dimensionality reduction in molecular association processes.

Main Methods:

• Derivation of exact equations for binding free energy terms.
• Application of the perturbation-divergence formalism (PDF).
• Utilizing Kullback-Leibler (KL) divergence to quantify dissipative energetic terms.

Main Results:

• Binding free energy (ΔG⁰) is precisely decomposed into average perturbation and dissipative terms.
• Dissipative terms are quantified using KL divergence and linked to configurational changes (translation, rotation, conformation).
• Identification of exactly canceling energetic terms that do not contribute to ΔG⁰.

Conclusions:

• The perturbation-divergence formalism (PDF) offers an exact method for calculating binding free energy.
• PDF provides a detailed understanding of energetic contributions, including solvation and conformational changes.
• PDF facilitates dimensionality reduction and connects dynamic processes with thermodynamic outcomes.