Phd in CHEMICAL SCIENCES

Thesis title: Modeling electronic and structural properties of nucleic acids in solution

The aim of this thesis is the development and the application of theoretical-computational approaches for the study of nucleic acid chemistry in solution. In detail, the oxidation-reduction chemistry involving the nitrogenous bases and the hydrolysis reactions of the phosphodiester bonds were explored. The redox reactions involving the DNA nucleobases constitute a class of phenomena particularly relevant in chemistry and biochemistry. In fact, they are involved in genome damaging processes and damage signaling, and for the technological applications where the DNA bio-polymer acts as a molecular conductive wire. The phosphodiester bonds, with their reluctance towards hydrolysis, are essential for maintaining the stability of the genome. At the same time, several enzymes, able to cleave and form this type of bonds, evolved in order to develop a finely tuned signaling strategy in living organisms. To describe and unveil mechanistic aspects about these phenomena, a description of the system within a statistical-mechanical based approach is needed to extract reliable thermodynamic and kinetic observables. In the first part of this work, we show a theoretical description, based on an hybrid quantum mechanics/molecular mechanics (QM/MM) method, of the thermodynamics and kinetics of one-electron oxidation reactions involving nucleobases, single- and double-stranded DNA oligomers in solution. We found that the sequence and the conformation of the nucleic acid has a strong influence on the redox properties of a single nucleobase in a strand and on the conduction properties of a double strand. More broadly, we proposed a general way to investigate the thermodynamics and the kinetics of such reactions taking into account the complexity of the system. In the second part, a general model based on the same QM/MM method to treat chemical reactions in solution was developed and applied to a model phosphodiester. Subsequently, in synergy with an experimental approach, we investigated the hydrolysis mechanism of an RNA-model compound on the whole pH scale, underlying that at different pH conditions different mechanisms are dominant. In this work, we developed and applied theoretical-computational schemes able to quantitatively model the described processes. The same computational procedures could be applied to treat other relevant aspects of nucleic acids chemistry.