Molecular Dynamics Simulations of Neutral Chlorpromazine in Zwitterionic Phospholipid Monolayers

Molecular dynamics simulations have been performed to investigate the interactions between chlorpromazine (CPZ), a neuroleptic drug used in the treatment of psychiatric disorders, and dipalmitoylphosphatidylcholine (DPPC), a zwitterionic phospholipid, in Langmuir monolayers. The results from simulat...

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Bibliographic Details
Published in:The journal of physical chemistry. B 2006-05, Vol.110 (17), p.8804-8814
Main Authors: Pickholz, Mónica, Oliveira, Osvaldo N, Skaf, Munir S
Format: Article
Language:English
Subjects:
1,2-Dipalmitoylphosphatidylcholine - chemistry
Chlorpromazine - chemistry
Computer Simulation
Membranes, Artificial
Models, Chemical
Models, Molecular
Molecular Structure
Surface Properties
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Summary:Molecular dynamics simulations have been performed to investigate the interactions between chlorpromazine (CPZ), a neuroleptic drug used in the treatment of psychiatric disorders, and dipalmitoylphosphatidylcholine (DPPC), a zwitterionic phospholipid, in Langmuir monolayers. The results from simulations carried out at different monolayer surface densities were able to capture important features of the CPZ−lipid interaction. We find that neutral (unprotonated) CPZ is preferentially located in the lipid tail region of the phospholipids, in little contact with the aqueous phase, and that the orientation of its rigid ring structure and tail conformation vary with lipid surface density. CPZ is found to promote ordering of the lipid tails for all surface densities because of a reduction in the effective surface area per lipid upon addition of the drug. Similar effects have been observed in previous studies of cholesterol in DPPC monolayers, in which lipid tails were seen to order around the solute. This feature, however, is quite distinct from what we observe for the most dense monolayer considered here (area per lipid of 50 Å2), for which we find that CPZ promotes a local distortion of the lipid tails in its immediate vicinity and a concomitant ordering of lipid tails located further away from the solute. This view is further supported by the results obtained for an approximated nonlinear vibrational sum frequency generation susceptibility, which showed greater tail disorder close to CPZ.
ISSN:1520-6106
1520-5207
DOI:10.1021/jp056678o