The methodology of parameterization of platinum-based drugs was developed. Parameterization of molecular complexes containing a metallic compound, such as cisplatin, is challenging due to the unconventional coordination nature of the bonds which involve platinum atoms. We developed a new methodology of parameterization for such compounds based on quantum dynamics (QD) calculations. We show that the coordination bonds and angles are more flexible than in normal covalent compounds. The influence of explicit solvent is also shown to be crucial to determine the flexibility of cisplatin in quantum dynamics simulations. Proposed methodology based on QD simulations provides a systematic way of building such topologies. Based on these findings we started development of the force fields for other platinum derivatives, namely carboplatin and oxaliplatin.
We introduced new technique for simulating membranes with the global membrane curvature restricted to any desirable value. We conduct a systematic analysis of the influence of curvature on various properties of a realistic model of mammalian plasma membrane with asymmetric lipid content of monolayers and a realistic concentration of cholesterol.
Experimental teams performed spectroscopic measurements of the most common membrane lipids and determined spectroscopic determinants of their phase and topological identity. Particularly reference spectra of major membrane lipids were recorded as well as the spectra of the lipid mixtures and the spectra of the lipids in presence of common anti-cancer drugs. The methodology of the surface-enhanved spectroscopy of adsorbed artificial liposomes is established.
The influence of lipid composition on the membrane proteins topogenesis was investigated. Particularly a Charge Balance Hypothesis for membrane protein orientation/topogenesis was tested in spectroscopic experiments. The new results confirm capability of approach to distinguish spectroscopically Gram-positive and Gram-negative bacteria pathogens. The lipid vibrational Infrared and Raman spectra of different bacteria will be used to build a library of reference spectra for lipid mixtures which correspond to lipid composition of common bacterial membranes.
New colorimetric non-radioactive assay for determining position of PE, PS and LPG lipids in different leaflets of the cell membrane was developed. A combination of fully membrane permeable and impermeable lipid labeling compounds were used to determine the sidedness of PE, PS and LPG lipids respectively in two step labeling without a detergent treatment which is required to estimate a total pool of these lipids in bilayer. This method can be used for probing outer-to-inner leaflet lipid asymmetry with better precision and reliability than existing techniques.
Experimental characterization of markers for tracking of changes in membrane-protein and membrane-drug was performed by Latvian team. Prospective spectral markers were established in IR spectra. The IR and Raman reference spectra of the basic membrane lipids were recorded for liposomes in solution and on enhancing gold surface. Based on this reference the influence of platinum anti-cancer drugs carboplatin and oxalyplatin on the structure of lipid membranes was investigated spectroscopically.
The following research activities were performed for studying the properties of the membrane proteins:
1. Investigation of the crowding effects of integral membrane proteins
2. Study of the role of hydrogen bonds in stabilisation of the photosynthetic reaction centre membrane proteins against hydrostatic high pressure.
3. Quantum chemical modelling of the bacterial photosyntetic reaction centre structure and spectra was performed.
4. Structural studies of artificial lipid membranes by X-ray and neutron reflectivity techniques were performed.
Spectral characterization of several types of nanomaterials, which are prospective for use as luminescent markers in biological membranes, was performed. Some prospective nanomaterials include Hexagonal boron nitride – hBN, Aluminum nitride (AlN) – undoped AlN and doped with rear earth (Tb, Eu) and Mn.
