Ph.D. Thesis Defense: Large-Scale and Linear-scaling Quantum Mechanics Computational Methods to Characterize the DNA G-quadruplexes and their interaction with small molecules

CIC nanoGUNE Seminars

Speaker

Iker Ortiz de Luzuriaga, Pre-doctoral Researcher, Theory Group

When

2023/03/03
12:00

Place

"Bergara Seminar", Faculty of Chemistry UPV/EHU

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**Large-Scale and Linear-scaling Quantum Mechanics Computational Methods to Characterize the DNA G-quadruplexes and their interaction with small molecules** Iker Ortiz de Luzuriaga Theory Group, CIC nanoGUNE G-quadruplexes have raised considerable interest in developing ther-apies against cancer during the last few years. These non-canonical structures of DNA may be found in telomeres and/or oncogene promoters, and it has been observed that the stabilization of such G-quadruplexes may disturb tumor cell growth. Nevertheless, the mechanisms leading to the folding and stabilization of these G-quadruplexes are still not well established, and they are the focus of current work in this field. In this thesis, the interaction of two isomers, equatorial and axial, of the [Mo(η3 -C3 H5 )Br(CO)2 (phen)] metal complex with different DNA structures was studied, taking particular interest in DNA G-quadruplexes. We use computational methods to gain insight into the experimentally found cytotoxicity. Among all the methods used, the Linear- Scaling Density Functional Theory has a particular relevance throughout the work. Still, techniques such as semi-empirical, DLPNO-CCSD(T), and QM/MM have also been used. Besides, we supplement the theoretical work employing EDA, QTAIM, and NCI analysis to get insight into the weak non-covalent interactions of these systems that modulate their affinity. Computed formation energies, energy decomposition analysis, solvation energies, and non-covalent interaction analysis explains the preference of the metal complex for the G-quadruplex DNA binding over the duplex DNA. We also observed that an axial complex is more favorable for interaction with the G-quadruplex DNA than the equatorial one. This is due to the conformation adopted by the axial complex, wholly inserted in the cavity of the G-quadruplex structure, disposed between tetrads, and favoring the establishment of stabilizing non-covalent weak interactions. The most relevant weak interactions correspond to π − π stacking ones because the phenanthroline ligand’s flat aromatic surface is perfect for interacting with the tetrads of the G-quadruplex DNA structure. On the other hand, we also found that the role of the ancillary ligands is crucial to enhance the interaction of the metal complex with DNA. **Supervisor:** Xabier Lopez Pestana (UPV/EHU) and Adria Gil Mestres