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Lipid-Small Molecule Interactions

Lipid-small molecule interactions are involved in many biological processes, such as:

• Partitioning across cell membranes
• Cell transport
• Antibiotics and other drugs binding to membranes
• Surfactant binding
• Metal binding
• Endotoxins

Knowledge of these interactions is important to understand how lipids function in biological systems. There have been rapid advances in structural biology and relating structure to biochemical function and mechanism. However, knowledge of protein and lipid structure alone does not ensure accurate prediction of function and biological activity. The complete characterization of any binding interaction requires a quantification of the affinity, number of binding sites, and the thermodynamics. 

Thermodynamic data, specifically enthalpy (ΔH) and entropy (ΔS), reveal the forces that drive complex formation and mechanism of action. Thermodynamics provide information on conformational changes, hydrogen bonding, hydrophobic interactions, and charge-charge interactions.  This information is used to describe the function and mechanism at a molecular level. 

Isothermal Titration Calorimetry (ITC) is a powerful analytical tool which measures the binding affinity and thermodynamics between any two biomolecules. ITC is considered the “gold standard” assay for binding.

ITC is vital in the study of multi-probe structure activity relationships (SAR) since it can detect contributions that affinity-only methods may miss.  For example, the affinity measured by these methods may be similar for a wild-type and mutant protein binding to a lipid but ITC can reveal differences in ΔH and ΔS that can describe the mechanism of action of binding.  This information can validate in-silico modeling. ITC is also commonly used to validate other binding assays.

When a ligand-like detergent interacts with a membrane, there are multiple heat changes associated with solute partitioning.

Since ITC is done in-solution, it can utilize any biological buffer, including detergent to solubilize the lipid. For a full characterization of a biomolecular interaction, it is important to observe how salt, pH, temperature, etc affects binding affinity and thermodynamics.

Some antibiotics and other drugs interfere with membranes. ITC is also becoming an important tool in characterizing drug-target interactions, and can be used in many different stages of Drug Discovery and Development.

ITC – Lipids-Small Molecule Interactions Reference List

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