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.

Abstract Spontaneous changes in protein systems, such as the binding of a ligand to an enzyme or receptor, are characterized by a decrease of free energy. Despite the recent developments in computing power and methodology, it remains challenging to accurately estimate free energy changes. Major issues are still concerned with the accuracy of the underlying model to describe the protein system and how well the calculation in fact emulates the behaviour of the system. This thesis is largely concerned with the quality of current free energy calculation methods as applied to protein-ligand systems. Several methodologies were employed to calculate Gibbs standard free energies of binding for a collection of protein-ligand complexes, for which experimental affinities were available. Calculations were performed using system description with different levels of accuracy and included a continuum approach, which considers the protein and the ligand at the atomic level but includes solvent as a polarizable continuum, and an all-atom approach that relies on molecular dynamics simulations. In most such applications, the effects of ionic strength are neglected. However, the severity of this approximation, in particular when calculating free energies of charged ligands, is not very clear. The issue of incorporating ionic strength in free energy calculations by means of explicit ions was investigated in greater detail and considerable attention was given to the affinities of charged peptides in the presence of explicit counter-ions. A second common approximation is concerned with the description of ligands that exhibit multiple protonation states. Because most of current methods do not model changes in the acid dissociation constants of titrating groups upon binding, protonation equilibria of such ligands are not taken into account in free energy calculations. The implications of this approximation when predicting affinities were analysed. Finally, when calculating free energies of binding, a correct description of the interactions between the protein and the ligand is of fundamental importance. However, active sites of enzymes, where strained conformations may hold a functional role, are not always accurately modelled by molecular mechanics force fields. The case of a strained planar proline in the active site of triosephosphate isomerase was investigated using an hybrid quantum mechanics/molecular mechanics method, which implies a higher level of accuracy.

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Catalysis is a key area of chemistry. Through catalysis it is possible to achieve better synthetic routes, exploit molecules normally considered to be inactive and also attain novel chemical transformations. The development of new catalysts is crucial to furthering chemistry as a field. Computational chemistry, arising from applying the equations of quantum and classical mechanics to solving chemical problems, offers an essential route to investigating the underlying atomistic detail of catalysis. In this thesis calculations have been applied towards studying a number of different catalytic processes. The processing of renewable chemical sources via homogeneous reactions, specifically cardanol from cashew nuts, is discussed. All routes examined for monoreduction of a diene model by [Ru(H)(iPrOH)(Cl)(C₆H₆)] and [Ru(H)(iPrOH)(C₆H₆)]⁺ are energetically costly and would allow for total reduction of the diene if they were operating. While this accounts for the need of high temperatures, further work is required to elucidate the true mechanism of this small but surprisingly complex system. Gold-mediated protodecarboxylation was examined in tandem with experiment to find the subtle steric and electronic effects that dictate CO₂ extrusion from gold N-heterocyclic carbene activated benzene-derived carboxylic acids. The origin of a switch in the rate limiting step from decarboxylation to protodeauration with less activated substrates was also clearly demonstrated. Studies of gold systems are closed with examinations of 1,2-difluorobenzene C–H activation and CO₂ insertion by [Au(IPr)(OH)]. Calculations highlight that the proposed mechanism for oxazole-derived substrates cannot be extended to 1,2-difluorobenzene and instead a digold complex offers more congruent predicted kinetics. The lens of quantum chemistry was turned upon palladium-mediated methoxycarbonylation reactions. An extensive study was undertaken to attempt to understand the bidentate diphosphine ligand dependency on forming either methylpropanoate (MePro) or copolymers. Mechanisms currently suggested in literature are shown to be incongruous with the formation of MePro by Pd(OAc)₂ and bulky diphosphines. A possible alternative route is proposed in this thesis. Four mechanisms for methoxycarbonylation with Pd(2-PyPPh₂)ₙ are detailed. The most accessible route is found to be congruent with experimental reports of selectivity, acid dependency and slight steric modifications. A modification of 2-PyPPh₂ to 2-(4-NMe₂-6-Me)PyPPh₂ is shown to improve both selectivity and turnover, the latter by four orders of magnitude (highest transition state from 22.9 kcal/mol to 16.7 kcal/mol ∆G), and this new second generation in silico designed ligand is studied for its applicability to wider substrate scope and different solvents. The final chapter of this thesis is a mixed quantum mechanics and molecular mechanics (QM/MM) examination of an enzymatic reaction, discussing the need for certain conditions and the role of particular amino acid residues in an S[sub]N2 hydrolysis reaction.