DUPLEX focuses on non-covalent interactions, which are pivotal in self-assembly and supra-molecular chemistry. We address the fundamental question of the nature of the stability of oligonucleotides (and ultimately DNA itself) based on model ab initio calculations. Since stability is not just due to intrinsic features and substituent effects in the gas phase we will link our work with molecular simulation studies. We will constantly contrast our findings with the extensive literature study on MD and MC simulations of oligonucleotides that we carried out already. However, due to the enormity of the central question and the limited time scale we will not perform simulations ourselves. Furthermore we envisage interacting with the large experimental group of a colleague in the School of Chemistry, called Prof DB Kell.
His lab has expertise in measuring melting curves obtained by UV spectrophotometry and microcalorimetry. This proposal builds on a paper we recently published in J.Am.Chem.Soc. [vol.124 p.8725 (2002 )] There are three objectives: (1) Determine the validity of Jorgensen well-cited secondary interaction hypothesis for a sizeable set of modified bases. (2) Establish the effect of substituent effects on the stability of H-bonded base pairs. (3) Via ab initio calculations estimate stacking interaction energies for natural bases and N6-methyladenosine and 5-methylcytosine.
Very recently computing power has reached the level where benchmark energies for a variety base pair configurations can be obtained from first principles. With state-of-the-art ab initio calculations we will obtain insight into pi-pi stacking for smaller model systems and at lower level for ribose/phosphodiester-linked base pairs. The rigorous partitioning theory called Quantum Chemical Topology will feature strongly. Epigenetics and important biological techniques such as PCR and Kunkel mutagenesis will benefit from the deeper understanding resulting from this project.
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