Conjugated molecules as optical probes for biomembranes: theoretical insights
Theoretical methods allow nowadays to deeply understand the biological activities of drugs. To continuously improve the biological prediction of this feature, molecular systems are simulated to approximate biological environment with increasing accuracy. Molecular dynamics is a promising tool to evaluate the ability of drugs or food nutrients with lipid bilayers. This characteristic is crucial as for many biological activities (e.g., drug metabolism and anticancer, antibacterial and antioxidant activities), the molecule has to be incorporated in the membrane or to cross it. The molecular dynamic simulations of lipid bilayer membrane associated to a drug allow evaluating the diffusion coefficients, the depth of the penetration and the orientation of the molecules. This tool appears to become crucial and efficient in future to provide a molecular picture, complementary to the experimental evidences (obtained e.g., by fluorescence or NMR). The current simulations of biological membranes are performed on relatively simple models usually made of a single lipid constituent e.g., dioleyl phosphatidyl choline (DOPC) and dipalmitoyl phosphatidyl choline (DPPC). One of the main challenges in this topic is to approach as close as possible to realistic/biological conditions. For this purpose, we propose to theoretically studying i) various lipid bilayers e.g., oxidized membranes, ii) mixture of lipids and iii) influence of sphingomyelin (SM) and cholesterol (Chol) brought into the membrane. Many methodological issues have to be evaluated to fully validate the membrane models including force fields to be used for the molecular dynamics, length of the free simulations, solvent models, calculations of the energy profiles along the penetration in the membrane. These theoretical developments will be achieved in close relation with experimentalists and experimental data. The correlation of theoretical and experimental data will be performed using fluorescent probes. Attention will be given to various lipid phases as well as phase transitions. After having investigated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (Bodipy) derivatives, we focus now upon 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindodicarbocyanine perchlorate (DiI-C18), which has been used as a fluorescent probe to investigate the lipid rafts in their liquid ordered, liquid disordered and gel phases. Also, temperature effects can be taken into account and a close comparison of computationally obtained data with experiments will be performed. At the current stage of our ongoing research upon this investigation, optical properties (absorption and fluorescence) are calculated at the quantum level. In doing so, as a major issue, the influence of the membrane will be theoretically evaluated. We plan to do QM/MM calculations with initially TDDFT as QM method, but it should be compared with CC afterwards.