Energetic and entropic factors determining binding affinity in protein-ligand complexes

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Non-covalent interactions in protein-ligand complexes are fundamental to biochemistry and drug discovery.
• Ligand affinity, ranging from 10-80 kJ/mol, is determined by enthalpic and entropic effects, influencing binding constants and free energy.
• Key interactions include hydrogen bonds and lipophilic contacts, significantly impacted by solvation and desolvation processes.

Purpose of the Study:

• To elucidate the critical factors governing protein-ligand interactions.
• To highlight the importance of enthalpic and entropic contributions to binding affinity.
• To discuss the role of solvation effects and the potential for non-additive behaviors in binding.

Main Methods:

• Analysis of enthalpic and entropic contributions to binding affinity.
• Examination of hydrogen bonds, lipophilic contacts, and solvation/desolvation effects.
• Consideration of additive group contributions and non-additive phenomena like conformational pre-organization.

Main Results:

• Enthalpic and entropic effects, particularly hydrogen bonds and lipophilic contacts, are primary drivers of protein-ligand binding affinity.
• Solvation and desolvation of ligands and binding sites are critical.
• Non-additive behaviors can arise from factors like ligand flexibility and conformational pre-organization.

Conclusions:

• A quantitative understanding of protein-ligand interactions requires considering additive group contributions, while acknowledging potential non-additive effects.
• Ligand flexibility and mobility significantly influence binding affinity.
• Experimental separation of enthalpy and entropy can yield surprising insights, such as entropy loss correlating with hydrogen bond loss.