Computational photochemistry of heteroaromatic biomolecules : photodynamic therapy and ultrafast relaxation

This thesis focuses on the photochemistry of heteroaromatic biomolecules. These molecular systems have a rich photochemistry and take part in photochemical reactions that have many very topical applications. Small heteroaromatics constitute important biological building blocks and are therefore a fundamental components of living organisms. Even though these compounds absorb light very efficiently, they also have ultrafast relaxation processes available to them. This means that they can remove the absorbed energy very fast and avoid harmfull photoproducts forming, which can lead to cell damage. Larger heteroaromatics have a similarly efficient absorption of electromagnetic light, and are present in compounds that are responsible for the harvesting of energy in nature, for example the chlorophyll molecule in green plants and bacteria. If large heteroaromatics are artificially presented to living cells however, the excess energy absorbed by these systems may also cause cell damage. This destructive force can however be utilised in therapy forms where there is a need to get rid of unwanted cells, such as in anti-cancer therapy. A form of therapy based on this principle is photodynamic therapy. The use of computational chemistry in the investigations of photochemical phenomena has increased following the improvements in the efficiency of computers and algorithms. Modern techniques have now reached a stage where ultrafast relaxation processes can be calculated for small heteroaromatics. As the experimental community has also reached a stage where these compounds can be probed using ultrafast laser experiments, there is a need for computational input to aid in the interpretation of the data of these phenomena. This thesis will present computational results concerning the relaxation dynamics of important small heteroaromatic biomolecules, and discuss them in terms of experimental data collected by collaborative groups. For the development of molecules to be used in photodynamic therapy, a lot of work is needed to ensure safety for use in human beings. With the computational chemistry community now being able to carry out absorption studies for large heteroaromatics, computational structure-absorption relationships can aid the development of this form of therapy. At the limits of modern photochemistry, methods are also appearing that can be used for studies of ultrafast relaxation in larger systems. These computations could contribute hugely to the understanding of the behaviour of these types of systems and aid their development. In a large component of this thesis, new structure-absorption relationships are presented for interesting heteroaromatics with potential for use in photodynamic therapy. One section is also devoted to exploratory work using methods that have not before been used in systems that are larger in size, and presents some promising results as well as current challenges in the field

Computational Modelling of the Steps Involved in Photodynamic Therapy

Photodynamic therapy (PDT) is a branch of phototherapy that has seen a surge of interest in the last few decades, due to its potential in the treatment of various cancers, infections and heart disease.(Bonnett, 2000) This chapter aims to give an overview of the various photochemical steps involved in PDT as a cancer therapy, and in particular the challenges and insight gained from their theoretical description. After a brief review of PDT in general, in a biological and chemical context, the photochemical steps involved will be discussed, detailing the computational techniques required to model these chemical pathways theoretically. We will detail the methodologies that can currently be applied, as well as their limitations of use at present, and areas requiring further development

Following the excited state relaxation dynamics of indole and 5-hydroxyindole using time-resolved photoelectron spectroscopy

Time-resolved photoelectron spectroscopy was used to obtain new information about the dynamics of electronic relaxation in gas-phase indole and 5-hydroxyindole following UV excitation with femtosecond laser pulses centred at 249 nm and 273 nm. Our analysis of the data was supported by ab initio calculations at the coupled cluster and complete-active-space self-consistent-field levels. The optically bright 1La and 1Lb electronic states of 1\u3c0\u3c0* character and spectroscopically dark and dissociative 1\u3c0\u3c3* states were all found to play a role in the overall relaxation process. In both molecules we conclude that the initially excited 1La state decays non-adiabatically on a sub 100 fs timescale via two competing pathways, populating either the subsequently long-lived 1Lb state or the 1\u3c0\u3c3* state localised along the N-H coordinate, which exhibits a lifetime on the order of 1 ps. In the case of 5-hydroxyindole, we conclude that the 1\u3c0\u3c3* state localised along the O-H coordinate plays little or no role in the relaxation dynamics at the two excitation wavelengths studied.Peer reviewed: YesNRC publication: Ye

Operon gene order is optimized for ordered protein complex assembly

SummaryThe assembly of heteromeric protein complexes is an inherently stochastic process in which multiple genes are expressed separately into proteins, which must then somehow find each other within the cell. Here, we considered one of the ways by which prokaryotic organisms have attempted to maximize the efficiency of protein complex assembly: the organization of subunit-encoding genes into operons. Using structure-based assembly predictions, we show that operon gene order has been optimized to match the order in which protein subunits assemble. Exceptions to this are almost entirely highly expressed proteins for which assembly is less stochastic and for which precisely ordered translation offers less benefit. Overall, these results show that ordered protein complex assembly pathways are of significant biological importance and represent a major evolutionary constraint on operon gene organization

Time resolved velocity map imaging of H-atom elimination from photoexcited imidazole and its methyl substituted derivatives

The photoresistive properties of DNA bases, amino acids and corresponding subunits have received considerable attention through spectroscopic studies in recent years. One photoresistive property implicates the participation of 1πσ* states, allowing electronically excited states to evolve either back to the electronic ground state or undergo direct dissociation along a heteroatom–hydride (X–H) coordinate. To this effect, time-resolved velocity map imaging (TR-VMI) studies of imidazole (a subunit of both adenine and histidine) and methylated derivatives thereof have been undertaken, with the goal of understanding the effects of increasing molecular complexity, through methylation, on the dynamics following photoexcitation at 200 nm. The results of these measurements clearly show that H-atom elimination along the N–H coordinate results in a bimodal distribution in the total kinetic energy release (TKER) spectra in both imidazole and it's methylated derivatives: 2-methyl, 4-methyl and 2,4-dimethylimidazole. The associated time constants for H-atoms eliminated with both high and low kinetic energies are all less than 500 fs. A noticeable increase in the time constants for the methylated derivatives is also observed. This could be attributed to either: ring methylation hindering in-plane and out-of-plane ring distortions which have been implicated as mediating excited state dynamics of these molecules or; an increase in the density of vibrational states at 200 nm causing an increased sampling of orthogonal modes, as opposed to modes which drive any dynamics that cause subsequent H-atom elimination. The results of these findings once again serve to illustrate the seemingly ubiquitous nature of 1πσ* states in the photoexcited state dynamics of biomolecules and their subunits