| Abstract |
The present thesis focused on the use of advanced molecular simulation techniques for the theoretical study of structural characteristics of different nanostructured systems as well as dynamic processes in which they are involved. Such methods enable studies in the atomistic scale (taking into account the interactions of particles) and the estimation of microscopic and macroscopic characteristics of the system under examination with high numerical accuracy and reliability. Nevertheless, atomistic-scale studies are quite challenging and have thus lead to the development of new techniques that can address the uniqueness of each system. One of the main goals of the current thesis has been to demonstrate the importance of molecular simulations (both simple and advanced techniques and their combinations), as an effective methodology for the study of materials and processes.
The systems studied varied from nanoporous carriers of active substances to biological membranes (lipid bilayers) also based on their relevance for highly important dynamic processes such as drug delivery. Lipid bilayers are the main component of many organs of a living organism (cellular membranes, skin etc.) and they play an important role as a barrier that regulates mass transfer mechanisms. On the other hand, nanoporous materials (silica- or carbon- based, metal-organic frameworks etc.) are gaining increased attention nowadays as effective matrices for hosting medicinal ingredients. It has been indeed shown that they can carry a great amount of active agents but also regulate the release of drug molecules. The latter renders those materials ideal to be used as controlled drug delivery systems. In this context, the current thesis used molecular simulation techniques to study different subsystems that may be relevant in a transdermal drug delivery process, i.e. an active agent carrier and a lipid bilayer membrane as an analogue of the outermost layer of skin. The structure and conformation of the lipid bilayer was studied alongside the diffusion and penetration of a drug substance (ibuprofen) through it. A second case study focused on the investigation of the release of ibuprofen from a well studied nanoporous matrice, such as MCM-41 nanospheres. All systems were simulated by appropriately adopting both simple and advanced molecular simulation techniques.
The core of molecular simulations is the way the interactions (inter / intra molecular) are modelled. A decisive phase of the current work, was the choice of the proper interactions of each system. In the case of lipid bilayers, a comparative study of five force fields (specialized for biological molecules) was performed using molecular dynamics. It was seen that CHARMM has the best performance and as such it was used for the main part of the simulations. Afterwards, the correlation between the lipids initial arrangement and the structural and dynamic properties of the finally formed bilayers was systematically studied. The vast majority of molecular simulations of lipids systems reported so far, begin with the construction of a fixed initial molecular bilayer arrangement (pre-constructed), which may result to a meta-stable thermodynamic state. However, in the present work, we also examined the effect of using as initial configuration, a self-assembled bilayer which is produced, with molecular dynamics, from a random initial distribution of lipids in an aqueous environment. The latter was created using the MARTINI Coarse Grained force field (assuming that interaction centers are groups of heavy atoms) followed by back-mapping to atomistic description using the CHARMM force field. It was found that the pre-constructed and the self-assembled bilayers have in general comparable structural properties.
Nevertheless they exhibit certain differences with respect to the packing and con-
formation of the aliphatic lipid chains, leading to a different energy barrier that
a drug molecule, such as ibuprofen, must overcome in order to move along the bilayer normal. These results show that the choice of the initial lipids setup for molecular dynamics simulations of a lipid bilayer may have significant impact on a part of the simulation outcome.
Aiming to address the part of a transdermal delivery process, where a drug substance is released from a nanoporous matrix , the system of MCM-41 / ibuprofen was studied. The porous material MCM-41 in the form of nanospheres has been shown to be a great candidate as drug carrier and its performance is often being used as benchmark for the discovery of new nanoporous materials that may be suitable matrices for the encapsulation of active agents. In the current thesis, the drug/matrix interactions were modelled with the CHARMM force field and advanced molecular dynamics techniques (Umbrella Sampling) were implemented.
Two phases of the whole process were simulated, i.e. the storage of the active agent inside the porous material (represented by pores filled with ibuprofen) and the release of the drug molecules in an aqueous environment. The results indicated a correlation of the diffusion coefficient with the concentration of the drug as well as with the environment inside the pore. Moreover, it was shown that the water molecules form stronger hydrogen bonds with the -OH of the pore wall surface , than ibuprofen. As such, water acts competitively and `pushes'
the molecules of ibuprofen outside the pore.
In the case of nanoporous carriers of drug substances, the interaction of the drug molecules with the surface of the pore, plays a key role both for the encapsulation mechanism and the release of the active agent. A common structural characteristic of porous materials is the so-called BET area value, which is calculated from the analysis of N2 adsorption/desorption data at 77K. In the case of microporous matrices, such as MOFs which are currently getting much attention study as drug nanocarriers, the low reproducibility of experimental calculations,
is a major problem in estimating the specific surface. In the current work, we addressed the latter by developing a novel computational method for defining and measuring the surface area inside the individual pores. The method was validated by comparing with a virtual sorption experiment (GCMC) and calculating the BET surface for a series of MOF crystals. The force fields UFF and PEA were used for the crystal structure and gas accordingly. The developed method has 15% deviation from GCMC results but it's 10 times faster for each pressure point (one Monte Carlo simulation) of the sorption isotherm curve, hence, it can
be used as a fast and reliable tool for the characterization of porous materials.
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