Protonation and orientation: a computational approach to cocaine diffusion through a model membrane

Area of Science:

• Biophysics
• Computational Chemistry
• Pharmacology

Background:

• Biological membranes control molecular passage.
• Protonable, amphiphilic molecules like cocaine present unique transport challenges.
• Understanding drug permeation is crucial for pharmacology and medicine.

Purpose of the Study:

• To investigate cocaine diffusion across a DMPC lipid bilayer.
• To compute free energy surfaces for protonated and neutral cocaine.
• To analyze the pH-dependent barriers affecting drug permeation.

Main Methods:

• Classical molecular dynamics simulations.
• Umbrella sampling technique for free energy calculations.
• Numerical solution of the diffusion equation.

Main Results:

• A membrane-spanning free energy barrier of 3.5 kcal mol⁻¹ was identified.
• pH-dependent entry (2.0 kcal mol⁻¹) and exit (4.1 kcal mol⁻¹) barriers were calculated.
• Membrane diffusion is 3.5 times slower than lateral diffusion, with a passage time of 0.1 ms.

Conclusions:

• Cocaine's passage through lipid bilayers is governed by its amphiphilic nature and pH-dependent protonation state.
• The identified barriers and diffusion rates offer insights into drug transport mechanisms.
• Findings have implications for drug delivery and crossing biological barriers like the blood-brain barrier.