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Bibliografija: str. 10-11. Abstract.

Effects of hydrophobicity and stereochemistry of poly(�-alkyl carboxylic acids) on the properties of TiO$_2$ suspensions were studied with experimental and in silico methods. Zeta potential measurements show that the addition of the more hydrophilic poly(acrylic acid) (PAA) to TiO$_2$ suspensions shifts the isoelectric point of the nanoparticles towards lower pH the most, followed by poly(methacrylic acid) (PMA) and poly(ethacrylic) acid (PEA). Stereochemistry has a less pronounced effect on suspension stability, except at low pH, where isotactic PMA (iPMA) is not soluble in water. Dynamic light scattering measurements show that the aggregate size of the nanoparticles correlates well with their zeta potential and the aggregates are largest at the isoelectric point of the nanoparticles. Molecular dynamics (MD) and Monte Carlo (MC) computer simulations were used to study the interaction of polyacids with the surface of nanoparticles. MD simulations show that PAA forms the largest amount of hydrogen bonds with TiO$_2$, followed by PMA. PEA forms very low numbers of hydrogen bonds with the nanoparticle surface. MC simulations were used to study the effect of pKa of COOH groups of polyacids on their adsorption on TiO$_2$. It was found that even small differences in pKa between the polyacids have a strong effect.

The modular software MOLSIM for all-atom molecular and coarse-grained simulations is presented with focus on the underlying concepts used. The software possesses four unique features: (1) it is an integrated software for molecular dynamic, Monte Carlo, and Brownian dynamics simulations; (2) simulated objects are constructed in a hierarchical fashion representing atoms, rigid molecules and colloids, flexible chains, hierarchical polymers, and cross-linked networks; (3) long-range interactions involving charges, dipoles and/or anisotropic dipole polarizabilities are handled either with the standard Ewald sum, the smooth particle mesh Ewald sum, or the reaction-field technique; (4) statistical uncertainties are provided for all calculated observables. In addition, MOLSIM supports various statistical ensembles, and several types of simulation cells and boundary conditions are available. Intermolecular interactions comprise tabulated pairwise potentials for speed and uniformity and many-body interactions involve anisotropic polarizabilities. Intramolecular interactions include bond, angle, and crosslink potentials. A very large set of analyses of static and dynamic properties is provided. The capability of MOLSIM can be extended by user-providing routines controlling, for example, start conditions, intermolecular potentials, and analyses. An extensive set of case studies in the field of soft matter is presented covering colloids, polymers, and crosslinked networks.

Izmed vseh molekul, ki jih najdemo v živih organizmih, so proteini najbolj zastopani in s funkcionalnega stališča najbolj raznoliki. Sestavljeni so iz dolgih verig aminokislin in na njihovo konformacijo, strukturo ter stabilnost lahko vplivajo številni parametri. Vodne raztopine proteinov običajno vsebujejo soli, najbolj pogosto v obliki pufra. Poleg proteinov, soli in vode pa so v bioloških sistemih pogosto prisotne še druge makromolekule (lipidi, sladkorji, nukleinske kisline), in to v znatnih koncentracijah. Vpliv zasedenosti prostora s temi makromolekulami lahko v laboratorijskih razmerah ponazorimo z dodatkom nevtralnega polimera polietilen glikola. Soli in druge molekule tudi vplivajo na interakcije molekul proteina z raztopino. Eden izmed načinov ugotavljanja teh interakcij je merjenje zeta potenciala. To delo zajema meritve zeta potenciala v raztopinah proteina lizocima, kjer je bil prisoten tudi polietilenglikol v različnih koncentracijah (0, 100 in 150 g/l) in pri treh vrednostih pH (4,1, 7 in 9). Vedno je bil prisoten enostaven elektrolit (10 mM NaBr). Viskoznost raztopin polietilenglikola narašča z njegovo koncentracijo in tudi z dolžino polimerne verige. Z naraščajočo koncentracijo pa se zmanjšuje dielektrična konstanta raztopine. Rezultati kažejo, da zeta potencial narašča s koncentracijo polietilenglikola pri vseh treh izbranih pH vrednostih. Zeta potencial narašča tudi z dolžino polimerne verige. Poleg lizocima sem uporabila tudi protein goveji serumski albumin. Tudi pri tem proteinu se zeta potencial z naraščajočo koncentracijo polietilenglikola po absolutni vrednosti povečuje. Pri pH 7 je namreč naboj BSA negativen. Rezultati meritev zeta potenciala v sistemih brez polietilenglikola so primerljivi s tistimi v literaturi. Meritve v prisotnosti polietilenglikola pa še niso bile narejene. Proteins are the most abundant molecules found in living organisms, and, from a functional point of view, also the most diverse. They consist of long chains of amino acids and their conformation, structure and stability can be influenced by many parameters. Aqueous solutions of proteins usually contain salts, most often in the form of a buffer. In addition to proteins, salt, and water, other macromolecules (lipids, sugars, nucleic acids) are often present in biological systems. In laboratory conditions, influence of these macromolecules can be mimicked by the addition of the neutral polymer polyethylene glycol. Salts and other molecules affect the interaction between protein molecules. One way to determine these interactions is by measuring the zeta potential. In this work, I measured the zeta potential in lysozyme protein solutions, where polyethylene glycol was also present in different concentrations (0, 100 and 150 g/L) and at three pH values (4,1, 7 in 9). 10 mM NaBr salt was used in all cases. The viscosity of polyethylene glycol solutions increases with its concentration and also with the length of the polymer chain. As the concentration increases, the dielectric constant of the solution decreases. The results show that the zeta potential increases with polyethylene glycol concentration at all three pH values. The zeta potencial also increases with the length of the polymer chain. In addition to lysozyme, I also used the protein bovine serum albumin. For this protein, the zeta potencial increases in absolute value with increasing polyethylene glycol concentration. At pH 7, the charge of bovine serum albumin is negative. The results of zeta potential measurements in systems without polyethylene glycol are comparable to those in the literature. However, measurements in the presence of polyethylene glycol have not yet been made.

Razvoj letalskega prometa ni vezan le na letala ampak tudi na vse dejavnosti, ki so posredno ali neposredno povezane z letenjem. Vedno bolj gost letalski promet je narekoval spremljanje vseh dejavnosti povezanih z letenjem, z namenom ugotavljanja šibkih in s tem nevarnih točk letenja. S pomočjo statističnih podatkov so regulatorni organi in organizacije sprejeli ukrepe za izboljšanje letalske varnosti. Pomemben element pridobivanja podatkov je nedvomno metodologija. Obdelava in vrednotenje podatkov pa sta elementa, ki dajeta pomemben doprinos k sprejemanju ukrepov s katerimi se vpliva na izboljšanje varnosti. The development of air traffic is not only related to airplanes, but also to all activities that are directly or indirectly related to flying. Increasingly dense air traffic dictated the monitoring of all activities related to flying, with the aim of identifying the weaks and the dangerous points of flying. With the help of statistical data, regulatory authorities and organizations have taken measures to improve aviation safety. An important element of data acquisition is undoubtedly the methodology. The processing and evaluation of data are elements that make an important contribution to the adoption of measures that influence the improvement of security.

Mobilni telefon je danes postal nepogrešljiv pripomoček v našem življenju. Ob nakupu telefona lahko v specifikacijah opazimo podatek SAR. Predstavlja kratico za stopnjo specifične absorpcije, ki določa količino absorbiranih visokofrekvenčnih elektromagnetnih sevanj v telesu zaradi izpostavljenosti mobilnemu telefonu. V posebnem laboratoriju lahko s pomočjo robota in človeku podobne lutke to tudi izmerimo. V kolikor telefon zadošča vsem predpisom in dosega dovoljene vrednosti, ga proizvajalci lahko ponudijo na trgovskih policah. Nekateri telefoni sevajo več, drugi manj. Obstaja pa tudi nekaj načinov, s katerimi lahko sevanje nekoliko omilimo. V diplomski nalogi sem primerjal SAR vrednosti telefonov različnih znamk, upoštevajoč različne parametre, in prišel do zaključka, da vsi upoštevajo dovoljene vrednosti. Ponudba pri slovenskih operaterjih je zelo pestra, zato me je zanimalo, kakšne so sevalne obremenitve (SAR) pametnih telefonov na slovenskem trgu, od česa je ta vrednost odvisna in kaj nam pove. Virtually everyone uses a mobile phone as an indispensable tool in the modern world. When buying a new phone, we can check the specifications for information about SAR value. SAR stands for specific absorption rate, describing the amount of high-frequency electromagnetic radiation reaching the body from a mobile phone. A special laboratory uses a robot and a human model to measure the amount of radiation received from a phone. Various phones have various SAR values, but all can be sold on the market if they don’t exceed the set limit. This diploma thesis compares the SAR value of popular mobile phones on the Slovenian market. I use several parameters to analyse and compare different brands and models of mobile phones, while also checking if the phones comply with the restrictions. As the market of modern mobile phones offers a wide variety of brands and models, I aim to analyse the most popular and widely used. I also present the theoretical background of electromagnetic radiation and the specifics of the SAR values and testing, which are applicable to all mobile phones.

Z računalniškimi simulacijami Monte Carlo sem izračunala kemijski potencial izotropnega 1:1 elektrolita v območju koncentracij med 0,02M do 1M. Z isto metodo sem izračunala tudi kemijski potencial istega elektrolita, ki se nahaja v nabiti reži. Hotela sem ugotoviti, kako naboj na stenah reže vpliva na koncentracijo soli v reži ter tudi, kakšna je struktura raztopine v njej. Ioni so bili v našem primeru toge kroglice, ki so imele nabojv središču. Spreminjala sem površinsko gostoto naboja na stenah reže, njeno širino in koncentracijo soli v njej. Z večanjem površinske gostote naboja na stenah reže se je kemijski potencial elektrolita v njej zmanjševal. Na osnovi enakosti kemijskega potenciala elektrolita v reži s kemijskim potencialom izotropnega elektrolita sem določila koncentracijo soli v reži, ki je v ravnotežju z izotropno raztopino. V nabiti reži je koncentracija elektrolita večja kot v izotropni raztopini. Ta razlika se veča z naraščanjem površinske gostote naboja. Ob stenah reže je močno povečana koncentracija ionov nasprotnega predznaka, medtem ko se ioni enakega predznaka nahajajo v osrednjem delu reže. A chemical potential of a bulk 1:1 electrolyte was calculated using Monte Carlo computer simulations in the concentration range from 0.02M to 1M. The same method was used to determine the chemical potential of 1:1 electrolyte confined in a charged slit. The goal was to determine the effect of surface charge densitiy on salt concentration in the slit. Ions were modeled as charged hard spheres. Slit width, surface charge density, and salt concentration were varied. With increasing surface charge density a chemical potential of the salt was lowered. Based on the equality of the chemical potential, the salt contentration in the slit in equilibrium with bulk electrolyte was determined. In the charged slit the salt concentration is larger than in the bulk. This excess increases with increasing surface charge density. Near the slit walls there is significantly increased concentration of ions of the opposite sign, while ions of the same sign repelled toward the slit center.

K-Ras4B je protein udeležen v celični signalizaciji. Prehajanje med dvema stanjema, GDP-vezanim aktivnim in GDP-vezanim neaktivnim, mu omogoča, da deluje kot molekulsko stikalo in regulira intenziteto in trajanje celičnih signalov, ki vodijo v celične odzive kot sta rast in diferenciacija celic ter inhibicija apoptoze. K-Ras4B je eden najpogosteje mutiranih proteinov v rakavih celicah. Kljub desetletja trajajočim poskusom, je bil do sedaj uspeh na področju razvoja učinkovin, ki bi preko inhibicije K-Ras4B delovale kot zdravilo proti raku, omejen. Za nadaljni razvoj inhibitorjev K-Ras4B je potrebno globoko razumevanje bioloških in kemijskih mehanizmov delovanja tega proteina. V aktivni obliki je K-Ras4B preko neurejene C-terminalne regije zasidran v celično membrano. Katalitična domena K-Ras4B z membrano interagira le prehodno. Pokazano pa je bilo, da katalitična domena z membrano pretežno interagira v določenih orientacijah. V nekaterih izmed teh orientacij je zaradi položaja membrane ovirana interakcija s proteini, ki so pomembni za signalno funkcijo K-Ras4B, kar bi lahko vplivalo na njegovo aktivnost. Več dosedanjih raziskav je bilo usmerjeno v določanje prisotnih orientacij in prehodov med njimi, vpliv različnih orientacij na interno dinamiko katalitične domene pa še ni bil raziskan. V magistrskem delu smo izvedli simulacije molekulske dinamike in pripadajočimi analizami strukturne dinamike K-Ras4B divjega tipa ter K-Ras4B z onkogeno mutacijo G12D v GTP- in GDP- vezanem stanju v vodi in v dveh orientacijah glede na membrano, ki sta bili eksperimentalno pokazani kot dve najpogosteje zasedeni orientaciji. Potrdili smo eksperimentalno opaženo dejstvo, da je pri G12D-K-Ras4B v primerjavi z divjim tipom stabilnost orientacije z α-vijačnicami, orientiranimi paralelno glede na membrano (H1), večja od stabilnosti orientacije z α-vijačnicami, orientiranimi pravokotno (P1). Opazili smo konformacijske prehode, ki bi lahko bili ugodni za izmenjavo GDP z GTP v K-Ras4B-GDP v H1. S kvaziharmonsko analizo smo pokazali, da vezava proteina na membrano poveča njegovo vibracijsko entropijo, kar bi lahko olajšalo konformacijske spremembe, pomembne za funkcijo proteina. Opazili smo nizkofrekvenčne normalne načine nihanja, ki so specifični za protein, vezan na membrano in se razlikujejo med različnimi orientacijami. V teh načinih so prisotni odmiki atomov v regijah, pomembnih za interakcijo z vezavnimi partnerji K-Ras4B in bi lahko kazali na preferenco za specifične funkcijsko pomembne konformacijske spremembe v proteinu na membrani. Naši rezultati dajejo vpogled v vpliv orientacije proteina glede na membrano na dinamiko K-Ras4B, kar bi lahko prispevalo k razvoju inhibitorjev K-Ras, ki bi delovali preko modulacije orientacijske preference v korist neaktivnih orientacij. K-Ras4B is a protein involved in cell signaling. By switching between active GTP-bound and inactive GDP-bound conformation, it functions as a molecular switch, regulating the intensity and the timescale of cellular signals leading to various cellular responses such as cell growth, differentiation and inhibition of apoptosis. K-Ras4B is one of the most frequently mutated proteins in human cancers. Despite decades of efforts, the success in treating cancer by inhibiting K-Ras4B has been limited. For further development of K-Ras4B inhibitors a deep understanding of the biological and chemical mechanisms of its actions is required. In its active form, K-Ras4B is anchored to the plasma membrane through a disordered C-terminal region. The catalytic domain interacts with the membrane transiently however, it has been shown, that the catalytic domain interacts with the membrane preferentially in a limited number of distinct orientations relative to the membrane. In some of the orientations, the interaction with proteins, important for signalling function of K-Ras4B, may be hindered by the membrane, which suggests, that the orientation could influence the activity of the protein. There has been a significant effort in characterizing the most populated orientations and their transitions, however, the effects of different orientations on the internal dynamics of the catalytic domain have not yet been investigated. In this study we performed molecular dynamics simulations with the corresponding analysis of structure and dynamics of K-Ras4B in wild type form and with an oncogenic mutation G12D in GTP- and GDP-bound states in water and in two orientations, which have been experimentally shown as the two dominant orientations. We have corroborated the experimentaly observed fact that in G12D-K-Ras4B the stability of the orientation with parallel helices (H2) relative to the membrane compared to the orientation with perpendicular helices (P1) is increased in G12D-K-Ras4B relative to the wild type. We observed conformational transitions that could be favorable GDP-GTP exchange in K-Ras4B-GDP in H1. Using quasiharmonic analysis we have shown, that the vibrational entropy of membrane-bound protein is increased, which could facilitate the conformational changes, important for protein function. We have observed low-frequency normal modes, which are specific for membrane-bound protein and differ between different orientations. These modes feature displacements of atoms in regions, important for interaction with K-Ras4B binding proteins and might indicate preferences for specific functional conformational changes on the membrane. Our results give insight into the effect of the membrane orientation on dynamics of K-Ras4B, which could contribute to the development of K-Ras4B inhibitors that would act by modulating the orientational preferences towards inactive orientations.

V diplomski nalogi smo izvedli Monte Carlo (MC) simulacije na ionskih sistemih med dvema zporednima zvezno in diskretno nabitima površinama. Tak sistem je približek, ki nam omogoča vpogled v interakcije med nabitimi delci. S simulacijami smo želeli ugotoviti, kako diskretizacija naboja na površinah vpliva na silo med dvema delcema v primerjavi s silo pri zvezni nabitosti. Preverili smo tudi, ali imajo različne vrste diskretizacije različen vpliv na silo. Pri diskretni razporeditvi naboja se na površini delcev gosto naberejo protiioni, zaradi česar bi pričakovali manjši odboj med delcema. Izračun osmotskega tlaka na podlagi kontaktnih vredosti koncentracijskih profilov protiionov pa je namesto tega prikazal močno odbojno silo. Na podlagi tega lahko sklepamo o neustreznosti te enačbe pri opisovanju modelov, kjer se na površini delca nahaja diskretno razporejen naboj. Med zvezno nabitimi stenami smo v skladu s teorijo pri ustreznih pogojih opazili efektivno privlačno silo. Za manjše diskretne naboje, ki so po površini razpršeni tako, da posnemajo zvezno razporeditev, smo opazili veliko ujemanje z zvezno razporeditvijo med tlaki in koncentracijskimi profili. Večjih razlik med mrežno in naključno mobilno razporeditvijo nismo opazili. In this diploma thesis, Monte Carlo (MC) simulations for an ionic system between two parallel uniformly and discretely charged plates were performed. This model system is an approximation which enables the study of interactions between same charged particles. The simulations were used to illustrate the differences that occur when discrete charge is introduced in place of a uniform charge. It was our aim to also test how different patterns of discrete charge influence the force. With discrete charge, counterions concentrate more towards the charged walls inducing a weaker repulsive force compared to the one observed for uniform charge. Calculations of pressure, based on the contact concentrations of counterions, however, predicted an even stronger repulsion. We must therefore conclude that for discretely charged particles this approach is unsuitable for the prediction of particle interactions. At suitable conditions, however, the same method was successful in predicting an effective attractive force for uniformly charged particles. When compared, smaller dispersed discrete charge (resembling the uniform charge) produced a strong similarity for both pressure and the concentration profiles to that of the uniform charge. We found no significant difference between the different discrete patterns of charge.

Diplomsko delo zajema predstavitev molekulskega modeliranja. Poznamo pet nivojev modeliranja, ki se razlikujejo po časovni lestvici, velikosti sistema in namenu uporabe. Predstavljeni so različni grobozrnati modeli, ki so jih uporabljali v izbranih raziskavah lipidnih membran. Tak model tvorimo tako, da več atomov združimo v en psevdo atom. Primeri različnih psevdo atomov so metilna skupina, benzenov obroč, aminokislinski ostanki. S pomočjo simulacij na opisanih modelih lipidnih membran so izračunane različne lastnosti, kot so debelina dvosloja, upogibni modul, modul stisljivosti območja, linearna in površinska napetost, konstanta bočne difuzije, hitrost prepustnosti vode po dvosloju, flip-flop hitrost idr. Na koncu pa je predstavljen del rezultatov, do katerih sem prišla z računalniško simulacijo v programu Molsim. The following thesis includes a presentation of molecular modelling. There are five levels of modelling, which differ in time scale, system size and purpose of use. Various coarse-grained models used in selected studies of lipid membranes are presented. Such a model is formed by combining several atoms into one pseudo atom. Examples of various pseudo atoms are methyl group, benzene ring, amino acid residues. Using simulations on the described models of lipid membranes, various properties were calculated, such as bilayer thickness, bending modulus, area compressibility modulus, linear and surface tension, lateral diffusion constant, the rate of permeation of water across the bilayer, flip-flop rate, etc. Finally, some of the results obtained with a computer simulation using the Molsim program are presented.