5-Aminolevulinic acid and derivatives thereof : properties, lipid permeability and enzymatic reactions

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date

Computational modeling of Protein based super-absorbents from waste

Hydrogels are used for various applications, for example as transporters in drug delivery, incontrol lenses, and as superabsorbent material in diapers.[1] Most synthetic produced hydrogelsare based on synthetic polymers. Even though they are efficient and cheap, they are notbiodegradable and sometimes even toxic.To produce more environmental friendly and biodegradable superabsorbent polymers (Bio-SAPs), other building blocks can be used, such as polysaccharides[2] and various proteinstructures, for example fish shells[3], collagen[4], soy protein[5] and egg protein[6]. Experimentalstudies at the University of Boras show that it is possible to produce Bio-SAPs from by-productsof ethanol production from ligno-cellulose.[2, 6, 7]2. MethodWe have studied the absorption properties of protein structures in silico as a comparison toexperimental studies. The NPT Gibbs Ensemble Monte Carlo (GEMC) simulation scheme withtwo phases is used in order to calculate the absorption capacity of the protein. Pure water wassimulated in the first GEMC-phase and the peptide in the second phase. The simulations weremade with SPC/E water model [8] and the AMBER99 atomistic force field for the peptides [9].Furthermore, mesoscopic studies with coarse grained force fields have been done.To facilitate faster computations, we used cell lists for the atom-atom interactions,configurational bias algorithm to build the water molecules and the peptide side-chains, and thecavity bias algorithm [10] for molecule insertions.Model peptides have been studied with varying secondary structure, temperature andprotonation (pH). We also plan to study how cross-links affect the absorption. One of the peptideswe study is a 20 amino acid long peptide called SSP1.[11] This peptide is designed to form afibrous structure a hydrogel, and its structure is well defined. We have also studied a peptidewhich changes secondary structure when changing the pH, and concentration.[12] This makes itpossible to compare absorption properties with respect to the secondary structure.3. ConclusionWe have simulated peptides with the Gibbs Ensemble Monte Carlo scheme in order to studythe water absorption rate dependent of structure, charge, pH and temperature. This information isuseful when developing new biodegradable superabsorbent materials

Simulation of α- and β-PVDF melting mechanisms

Molecular dynamics (MD) simulations have been used to study the melting of α- and β-poly (vinylidene fluoride) (α- and β-PVDF). It is seen that melting at the ends of the polymer chains precedes melting of the bulk crystal structure. Melting of α-PVDF initially occurs via transitions between the two gauche dihedral angles (G ↔ G′) followed by transitions between trans and gauche dihedral angles (T ↔ G/G′). Melting of β-PVDF initially occurs via T → G/G′ transitions and via transitions of complete β- (TTTT) to α- (TGTG') quartets. The melting point of β-PVDF is higher than that of α-PVDF, and the simulated melting points of both phases depend on the length of the polymer chains used in the simulations. Since melting starts at the chain ends, it is important to include these in the simulations, and simulations of infinitely long chains yield melting points far larger than the experimental values (at least for periodic cells of the size used in this work), especially for β-PVDF. The simulated heats of fusion are in agreement with available experimental data

Permeability of 5-aminolevulinic acid oxime derivatives in lipid membranes

The endogenous molecule 5-aminolevulinic acid (5ALA) and its methyl ester (Me-5ALA) have been used as prodrugs in photodynamic treatment of actinic keratosis and superficial non-melanoma skin cancers for over a decade. Recently, a novel set of 5ALA derivatives based on introducing a hydrolyzable oxime functionality was proposed and shown to generate considerably stronger onset of the photoactive molecule protoporphyrin IX (PpIX) in the cells. In the current work, we employ molecular dynamics simulation techniques to explore whether the higher intercellular concentration of PpIX caused by the oxime derivatives is related to enhanced membrane permeability, or whether other factors contribute to this. It is concluded that the oximes show overall similar accumulation at the membrane headgroup regions as the conventional derivatives and that the transmembrane permeabilities are in general close to that of 5ALA. The highest permeability of all compounds explored is found for Me-5ALA, which correlates with a considerably lower fee energy barrier at the hydrophobic bilayer center. The high PpIX concentration must hence be sought in other factors, where slow hydrolysis of the oxime functionality is a plausible reason, enabling stronger buildup of PpIX over time

Simulations of the thermodynamics and kinetics of NH3 at the RuO2 (110) surface

Ruthenium(IV)oxide (RuO2) is a material used for various purposes. It acts as a catalytic agent in several reactions, for example oxidation of carbon monoxide. Furthermore, it is used as gate material in gas sensors. In this work theoretical and computational studies were made on adsorbed molecules on RuO2 (110) surface, in order to follow the chemistry on the molecular level. Density functional theory calculations of the reactions on the surface have been performed. The calculated reaction and activation energies have been used as input for thermodynamic and kinetics calculations. A surface phase diagram was calculated, presenting the equilibrium composition of the surface at different temperature and gas compositions. The kinetics results are in line with the experimental studies of gas sensors, where water has been produced on the surface, and hydrogen is found at the surface which is responsible for the sensor response

Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase

Schiff bases are common and important intermediates in many bioenzymatic systems. The mechanism by which they are formed, however, is dependent on the solvent, pH and other factors. In the present study we have used density functional theory methods in combination with appropriate chemical models to get a better understanding of the inherent chemistry of the formation of two Schiff bases that have been proposed to be involved in the catalytic mechanism of porphobilinogen synthase (PBGS), a key enzyme in the biosynthesis of porphyrins. More specifically, we have investigated the uncatalysed reaction of its substrate 5-aminolevulinic acid (5-ALA) with a lysine residue for the formation of the P-site Schiff base, and as possibly catalysed by the second active site lysine, water or the 5-ALA itself. It is found that cooperatively both the second lysine and the amino group of the initial 5-ALA itself are capable of reducing the rate-limiting energy barrier to 14.0 kcal mol−1. We therefore propose these to be likely routes involved in the P-site Schiff-base formation in PBGS

Time evolution of the CO2 hydrogenation to fuels over Cu-Zr-SBA-15 catalysts

Time evolution of catalytic CO2 hydrogenation to methanol and dimethyl ether (DME) has been investigated in a high-temperature high-pressure reaction chamber where products accumulate over time. The employed catalysts are based on a nano-assembly composed of Cu nanoparticles infiltrated into a Zr doped SiOx mesoporous framework (SBA-15): Cu-Zr-SBA-15. The CO2 conversion was recorded as a function of time by gas chromatography-mass spectrometry (GC-MS) and the molecular activity on the catalyst’s surface was examined by diffuse reflectance in-situ Fourier transform infrared spectroscopy (DRIFTS). The experimental results showed that after 14 days a CO2 conversion of 25% to methanol and DME was reached when a DME selective catalyst was used which was also illustrated by thermodynamic equilibrium calculations. With higher Zr content in the catalyst, greater selectivity for methanol and a total 9.5% conversion to methanol and DME was observed, yielding also CO as an additional product. The time evolution profiles indicated that DME is formed directly from methoxy groups in this reaction system. Both DME and methanol selective systems show the thermodynamically highest possible conversion.Funding agencies: EUs Erasmus-Mundus program (The European School of Materials Doctoral Programme - DocMASE); Knut och Alice Wallenbergs Foundation [KAW 2012.0083]; Swedish Government Strategic Research Area (SFO Mat LiU) [2009 00971]; Swedish Energy Agency [42022-1]</p