Properties and Permeability of Hypericin and Brominated Hypericin in Lipid Membranes

Abstract

The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy. Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine.

Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes

“…Hypericin releases reactive oxygen species in response to light, and may be used in laser‐assisted treatment of lipid capsules containing viruses (such as HIV), and many cancers, such as skin cancer. In MD simulations, the native form of hypericin adsorbs to the interface of lipid membranes . The molecule forms multiple hydrogen bonds with the water molecules even when membrane‐bound.…”

“…The hypericins aggregate in the water phase, and an adsorbed aggregate does not disintegrate in the membrane. Brominated hypericin settles deeper into the membrane and penetrates the whole membrane, enabling hypericin to possibly reach intracellular organelles . This effect is more pronounced in membranes containing a physiological amount (23%) of cholesterol than in systems with lower cholesterol content.…”

Investigating the effect of poly-l-lactic acid nanoparticles carrying hypericin on the flow-biased diffusive motion of HeLa cell organelles

“…It is well‐investigated that PLLA NPs are potential delivery systems for different photosensitizers in PDT . However, more attention has to be devoted specifically to understand their intracellular dynamics, localization and interactions with different cell organelles.…”

“…It is well-investigated that PLLA NPs are potential delivery systems for different photosensitizers in PDT. [49][50][51][52] However, more attention has to be devoted specifically to understand their intracellular dynamics, localization and interactions with different cell organelles. We used the ensemble-oriented techniques of temporal and spatiotemporal image correlation and cross-correlation spectroscopy to explore the dynamic interactions of the PLLA-hyp NPs with the early endosomes, late endosomes, lysosomes and mitochondria in living HeLa cells.…”

Testing Physical Models of Passive Membrane Permeation

“…However, it remains difficult to predict absolute permeability by this underutilized approach, which is as yet computationally too expensive to be practically applied in drug design. 29,35 A less computationally intensive alternative is to augment QSPR models with membrane-interaction descriptors obtained from MD simulations of permeants in lipid layers, such as the membrane-interaction QSAR method developed by Hopfinger and coworkers. 37–41 Another approach is to use coarse-grained or implicit membrane models, 42–49 which in principle provide an adequate representation of the membrane environment with lower computational expense.…”