Chlorpromazine interaction with phosphatidylserines: a (13)C and (31)P solid-state NMR study

Area of Science:

• Biochemistry
• Biophysics
• Pharmacology

Background:

• Chlorpromazine (CPZ) is an antipsychotic drug that antagonizes dopaminergic receptors.
• Phenothiazine derivatives, like CPZ, are cationic and amphiphilic.
• Understanding drug-lipid interactions is crucial for drug efficacy and delivery.

Purpose of the Study:

• To investigate the interaction of Chlorpromazine (CPZ) with phospholipid bilayers using solid-state NMR.
• To determine the binding sites of CPZ within different phospholipid compositions.
• To elucidate the role of phospholipid acyl chain unsaturation in CPZ-bilayer interactions.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy using (13)C and (31)P nuclei.
• Preparation of phospholipid bilayers with varying compositions: DPPC/PBPS and POPS/PBPS, with and without CPZ.
• Analysis of NMR spectra to infer molecular interactions and dynamics.

Main Results:

• CPZ preferentially binds to the phosphate group of phosphatidylserine.
• In DPPC/PBPS bilayers, CPZ also interacts with the carboxyl group of the serine head group.
• Acyl chain unsaturation in phosphatidylserine affects the motion of the serine head group, suggesting intermolecular restrictions.
• Specific acyl chains (e.g., 22:6 in PBPS) influence CPZ-induced bilayer interdigitation.

Conclusions:

• CPZ interacts with phospholipid bilayers, with a preference for phosphatidylserine head groups.
• The physical properties of phospholipid acyl chains, particularly unsaturation, modulate CPZ binding and its effects on bilayer structure.
• These findings provide insights into the molecular mechanisms underlying CPZ's interaction with cell membranes.