Abstract
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 headgroup 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 x 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 headgroup region. Trimethylpsoralen (TMP) has a very low free energy barrier to transversion, only approximately 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 x 10(-8) cm s(-1) for TMP to 4.1 x 10(-12) cm s(-1) 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 ultraviolet-A treatment.