Synergism of Computational and Experimental Methods: Rationalization of Empirical Observations based on Molecular Modelling

The interplay of experimental and computational methods assumes increasing importance in science as the computational power and the efficiency of theoretical models increase. Today, supplementing experiments with calculations is essentially indispensable in the understanding of fundamental questions related to chemistry. This thesis covers the outcome of three such studies, where molecular modelling is used as a practical tool to gain deeper understandings of empirical observations.

In Paper I, variations of hybrid models are applied to compute the absorption spectra of two solvated chromophores. In hybrid models, only the most relevant part of the system is treated with quantum chemistry, whereas the remaining parts are represented with an embedding potential achieved from either discrete or continuum models. A special focus in this study is to evaluate the combination of the Frenkel exciton approach and Polarizable Embedding. As model systems, two analogs of the chromophore from the photoactive yellow protein (PYP) are applied. It is confirmed that the Polarizable Embedding scheme performs similarly to full quantum chemical calculations for systems of which the solvent and solute absorption spectra are well separated. Of particular interest, it is shown that the spectral discrepancies (arising from excited state electronic energy transfers between solute and solvent molecules) can be minimized by applying the Frenkel exciton approach in combination with Polarizable Embedding. Thus, it is found that the whole absorption spectrum can be efficiently reproduced under reduced costs, even for chromophore-solvent systems where the individuel absorption spectra of chromophore and solvent are overlapping.

Paper II covers the synthesis and characterization of nucleic acids comprising nucleotides that contain two nucleobases (”double-headed nucleotides”). These artificial nucleotides can potentially condense the information of two separate nucleotides into one. The synthesis and biophysical characterization have not been a subject for this thesis, which only covers the molecular dynamics simulations and the analysis hereof. The aim of the simulation study is to get structural insights into how double-headed nucleotides are accommodated in the DNA double helix. An array of standard geometric parameters are measured and compared to the normal DNA helices. Furthermore, a deeper insight into the double-headed nucleotides’ binding mode is provided, including simulations of non-complementary DNA sequences in which a G-mismatch is installed opposite to the double-headed nucleotides. The overall results from the computational study show that the double-headed nucleotides are well accommodated in the helix core similar to the natural dinucleotides. The computational findings are in agreement with the experimental, biophysical results.

In Paper III, the optical properties of two C5–modified pyrimidine nucleosides are investigated. For this purpose, a combined experimental and computational approach is applied, where the latter is based on Born–Oppenheimer molecular dynamics and time-dependent density functional theory. A solid agreement is found between the experimental and computational results, and both methods prove that the nucleosides exhibit incredibly large Stokes shifts. By recording the fluorescence spectra in different solvents, it is in addition found that the Stokes shifts decrease along with the relative polarity of the solvents. The large Stokes shifts are explained by an excited state alignment of the two aromatic rings attached to the C5-position. Such alignment is probably induced by an increase in the bond order of the linking bond between the two rings. This will fulfill the requirements for better conjugation which again lowers the excited state energy and therefore explains the large Stokes shifts. Additionally, relative quantum yields as well as molar attenuation coefficients are derived from the experimental measurements.