BIOPHYSICAL THEORY AND MODELING |
Permeability of Psoralen Derivatives in Lipid Membranes
Daniel J.V.A. dos Santos 1 and Leif A. Eriksson 2*
1 Technical University Darmstadt
2 Örebro university
* To whom correspondence should be addressed. E-mail: leif.eriksson{at}nat.oru.se.
Submitted on November 28, 2005
Revised on January 26, 2006
Accepted on 6 July 2006
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Abstract |
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Molecular dynamics simulations have been performed to explore the distribution and translocation of a set of furocoumarins (psoralen derivatives) inside saturated and partially unsaturated lipid membranes. Within the simulations, strong accumulation of the photodynamic drugs is observed near the polar head-group region, although the populations also extend out into the membrane/water interface as well as to the membrane center. The computed transverse (Dz) diffusion coefficients are in the range 0.01 - 0.03 · 10-5 cm2 s-1; significantly slower than those reported for small molecules like water, ethane and ammonia, and are related to the low mobility inside the polar head group region. Trimethyl psoralen (TMP) has a very low free energy barrier to transversion, only ca 10 kJ/mol, whereas 5- and 8-methoxy psoralens (5-MOP, 8-MOP) have the largest barriers of the compounds studied; between 25 and 40 kJ/mol. Upper bounds to the permeation coefficients, obtained by integrating the resistance profiles across the bilayers, range from 5.2 · 10-8 cm/s for TMP to 4.1 · 10-12 cm/s for 5-MOP. The current simulations explain the high level of furocoumarin - lipid membrane complexes found in experimental studies of albino Wistar rats exposed to topical application of 8-MOP, and points to the possibility of membrane photodamage as a viable mechanism in psoralen UV-A (PUVA) treatment.
Key Words:
Furocoumarins, Lipid membranes, MD simulations, Photodynamic therapy (PDT), Translocation
