Studentská vědecká konference

Limited bioavailability of numerous active pharmaceutical ingredients (APIs) caused by a poor solubility of their crystals in water impedes their wider use. Amorphous dispersions with biocompatible polymers offer a solution to overcome this issue. We  aim at modeling a binary system containing sulfathiazole as an example of poorly soluble API, and polylactic acid (PLA) as a representative of a biocompatible polymer. Molecular dynamics simulations are used to investigate the properties of these substances. At first we start with simulating a polymer and API separately to validate various simulation settings and find out the best arrangement. For PLA, the effect of chain length, polydispersity, thermal history and initial conformation is studied. Further calculations are provided to obtain the glass transition temperature ($T_g$), densities, and the root mean square distance of the polymer chain termini. Force field files for sulfathiazole and PLA used during the simulations are then verified by comparison with experimental values. 

Lipases are enzymes that catalyze hydrolysis of the ester bonds in fats. They are an essential part of lipid metabolism of the living organisms, but they also have industrial applications. Due to their ability to function in both water and organic solvents, they can be utilized for synthetic reactions such as transesterification or aminolysis. Their activity, chemo-, regio- and enantioselectivity are highly valued. Enantioselectivity is the ability of an enzyme to distinguish between the two enantiomers (not identical mirror images) and favor only one for the reactions. Interestingly, it can be affected by solvent, which is the subject of our research. To obtain molecular level insight into the solvent effects on enantioselectivity of Candida Antarctica lipase B, we used molecular dynamics simulations. We generated trajectories for the lipase with bound substrates in three different solvents and analyzed the type and number of interactions of substrates with their environment. This will allow us to better understand the catalytic abilities of lipase for synthetic purposes.  

Density profiles of liquid-vapor interfaces far from critical point (Tc) are commonly interpreted in the context of capillary wave theory (CWT). We investigate the behavior of interfaces close to Tc, and the validity of CWT at high temperatures. The first model is the CWT-predicted sharp surface, while the second one assumes a flat region that smoothly transitions between the liquid and vapor densities. We analyze MD simulations by directly comparing them to the two model interfaces at different tempertures. We compute the distributions and the normal-direction profiles of a range of properties, such as the number of neighboring atoms within a certain radius, the Voronoi volume of the particles along with its asphericity and the intrinsic surface.  

The oral bioavailability of many drugs is very limited due to their low aqueous solubility when present in the crystalline form. One of the approaches to improve the oral bioavailability is the transformation of crystalline phase into amorphous state. However, pure amorphous forms tend to recrystallize in a very short time due to their metastability. Therefore, it is important to stabilize amorphous drugs using suitable biocompatible excipients such as polymers. So called amorphous solid dispersions (ASDs), in which drug is mixed with a polymer at the molecular level belong among the most promising strategies for enhancing the oral bioavailability. In this study, the thermodynamic and kinetic phase behavior of paclitaxel with selected biocompatible polymers was investigated to identify the most promising excipient for the development of paclitaxel formulation in a form of ASD. The solubility of paclitaxel in polymers, defining the thermodynamic stability of ASDs, and glass transition temperatures, defining the kinetic stability of ASDs, were studied by differential scanning calorimetry. The experimental solubility data were compared with the prediction using the quantum chemical model COSMO-RS as part of the evaluation of its performance in modeling drug-polymer phase diagrams.  

Žlučové barvivo bilirubin je lineární tetrapyrrol, který přirozeně vzniká v tělech savců jako konečný produkt katabolismu hemu. Vysoká koncentrace bilirubinu v těle je příčinou novorozenecké žloutenky, která se standardně léčí fototerapií. Při ní se molekuly bilirubinu v důsledku interakce se zářením přeměňují na polárnější produkty, které tělo snadněji vyloučí. V této práci jsou provedeny první kroky ke studiu mechanismu této fotochemické reakce pomocí metod kvantové chemie a molekulových simulací. V první fázi mého projektu byla provedena konformační analýza molekuly bilirubinu. Dále byly vypočteny energie zbývajících konfigurací molekuly. Byla také studována molekula lumirubinu, strukturního isomeru bilirubinu. V další fázi byl studován bilirubin v excitovaném stavu a analyzovány elektronové přechody. Výpočty základních stavů byly prováděny pomocí kombinací předběžných optimalizací semiempirickou metodou PM6 a následnou optimalizací DFT metodou B3LYP s bází 6-31g*, excitované stavy byly vypočteny metodou TD-DFT.  Na závěr byla provedena dynamická simulace molekuly v základním stavu a simulace molekuly v excitovaném stavu metodou OM3. Konečným cílem práce je objasnění mechanismu fotochemické reakce bilirubinu a návrh ultrarychlých laserových experimentů k jejímu potvrzení.  

Porous liquids (PLs) represent a new group of materials as they combine the permanent porosity of solid sorbents and the fluid properties of liquids. This work presents a molecular dynamics simulation addressing structural and thermodynamic properties of metal-organic frameworks (MOFs) and ionic liquids (ILs) with potential to compose a porous liquid. ILs with varying molecular sizes and a particular MOF pattern substituted with several metal ions are considered. Properties of both incriminated material classes are examined separately. To validate the accuracy of predictions of structural parameters, densities are evaluated for several temperatures and pressures and compared with their experimental counterparts. While a close agreement of theory and experiment is reached for ILs, the used force field for the MOFs is unable to reproduce the negative thermal expansion. It is shown that the ion pairs are presumably too voluminous to enter the cavities of MOFs. The prediction is based on effective molecular dimensions of ILs, the size of which exceeds the available aperture dimensions in the considered MOFs. That leaves potential for adding structured voids into liquids which is highly attractive in terms of promising applications including gas capture, catalysis, and separations.

Ferrocene is an organometallic compound, formed by a central Fe atom and two η⁵-cyclopentadienyl ligands. It is used in applications as a ligand scaffold, a non-toxic substitute for lead additives in fuels and as a standard electrode in electrochemistry. In my work, I focus on exploring the electronic structure of ferrocene using novel technologies of liquid state PES. The work aims at a theoretical interpretation of XAS obtained with this new technique. I specifically concentrate on the metallic L-edge, which arises as a result of the excitation of electrons from the 2p orbitals of the metal into the 3d orbitals, respectively into molecular orbitals with 3d character. For this purpose, I use techniques based on DFT as well as more demanding multireference approaches (CASSCF) using program ORCA. I focus on the influence of the type of solvent used, the conformation, the type of functional and the substituents. I have also performed calculations taking into account relativistic effects and thermal motion of the molecule using the Wigner sampling technique. We then compared the theoretically predicted spectra with the experimentally obtained spectra measured at the BESSY II synchrotron at the Helmholtz-Zentrum Berlin für Materialien und Energie using the liquid flat-jets technique.  

Liquid ammonia dissolves alkali metals, producing blue or bronze solutions depending on concentration. These solutions consist of alkali metal cations and electrons localized in solvent cavities between solvent molecules. They are used in organic chemistry, for instance in the Birch reduction. It is known from the experiments that the smallest stable cluster containing a solvated electron, is composed of 13 ammonia molecules. On the other hand, the reported theoretical calculations on ideal clusters at 0 K show that the needed number of ammonia molecules is 6.  Previously performed gas-phase 0 K optimizations of symmetric clusters, containing from 2 to 8 ammonia molecules with one excess electron have shown, that 4-5 ammonia molecules can stabilize one excess electron. However, these 0 K ideal structures don’t reflect the real finite temperature experimental structures and therefore carry no information about their electronic stability. Ab-initio molecular dynamics simulation of the 2 to 48 ammonia molecules with excess electron was performed in order to obtain the thermal structures of the small experimental clusters. The obtained structures were used to study the electronic stability of the finite temperature clusters by calculating their vertical detachment energy (VDE).