Enthalpy of captopril-angiotensin I-converting enzyme binding

Area of Science:

• Biochemistry
• Enzyme kinetics
• Pharmacology

Background:

• Angiotensin-converting enzyme (ACE) plays a crucial role in the renin-angiotensin system.
• Captopril is a well-known ACE inhibitor used in treating hypertension.
• Understanding the molecular interactions between ACE and captopril is vital for drug development.

Purpose of the Study:

• To investigate the thermodynamic and molecular basis of captopril binding to ACE.
• To quantify enthalpy, heat capacity, and protonation changes during captopril-ACE interaction.
• To elucidate the role of specific amino acid residues and binding sites.

Main Methods:

• High-sensitivity titration calorimetry was employed to measure thermodynamic parameters.
• Enthalpy changes were determined at various pH values.
• Protonation events and heat capacity changes were analyzed.

Main Results:

• Captopril binds to two sites on monomeric ACE with high affinity.
• Binding is enthalpically unfavorable but entropically favorable, driven by electrostatic and hydrophobic interactions.
• A significant heat capacity change (ΔCp = -4.3±0.1 kJ/K/mol) indicates enthalpy-entropy compensation.
• Protonation of an imidazole group, likely from histidine residues near the Zn2+ active site, was observed.

Conclusions:

• The binding of captopril to ACE is characterized by a complex interplay of enthalpy and entropy.
• Hydrophobic interactions and potential dehydration at the ligand-protein interface contribute significantly to binding.
• The observed enthalpy-entropy compensation, driven by a large negative ΔCp, influences the overall binding free energy.