My interest in cancer research began in 2011 when I joined - thanks to the “Erasmus Placement” fellowship - the group of Prof. Francesco Gervasio at the Dept. of Structural and Computational Biology at Cnio Centro Nacional De Investigaciones Oncológicas, Madrid (Spain). In his group I kept in touch, for the first time, with molecular dynamics simulations techniques, which allowed me to perform a structural investigation of HIV (type I and II) reverse transcriptases (RT) for the discovery of new anti-viral drugs to treat viral infections in patients with cancer. Subsequently, in 2013, I joined the group of Prof. Matteo Dal Peraro at the Bioengineering Institute of the Swiss Federal Institute of Technology Lausanne (EPFL), where I had the opportunity to further consolidate my computational background focusing on classical molecular dynamics simulations, well-tempered metadynamics and steered molecular dynamics, to name few of them.
In the group of Prof. Dal Peraro I started a project focused on the two-metal-aided function of Human DNA Polymerase-η, an enzyme that bypasses DNA lesions to guarantee correct genetic inheritance. Interestingly, in that period, Human DNA Polymerase-η (Pol-η) was found aberrantly expressed in melanoma cells and therefore the discovery of a potent Pol-η inhibitor was a challenge of great scientific interest. For this reason, in 2013, I moved in the group of Dr. Marco De Vivo at Dept. of Drug Discovery and Development of the Fondazione Istituto Italiano di Tecnologia where I started my PhD in the field of metalloenzymes such as Pol-η. Thanks to the collaboration between IIT and EPFL part of these results were recently published on Nucleic Acids Research (Genna et al. DOI: 10.1093/nar/gkw128, cover article).
Once having described the overall physical properties of Pol-η, we decided to investigate the reaction mechanism carried out by Pol-η to chemically extend damaged DNA. To accomplish this aim, in 2015 - thanks to the “Marco Polo” fellowship - I moved in the group of Prof. Paolo Carloni, director of the Institute of Advanced Simulation at Forschungszentrum Jülich, Germany. The group of Prof. Carloni is one of the most important players in the field of Car-Parrinello quantum-mechanics/molecular-mechanics (CP QM/MM) simulations, an expensive computational approach which allows, differently to classical simulations, the detailed investigation of the breaking/forming chemical bonds involved in reaction mechanisms. To perform CP QM/MM simulations we wrote and won two important grants funded by the John von Neumann Institute for Computing for a total of 1.5 million core-hours. In both case I was the leading author of the grant application. By means of CP QM/MM simulations we were able to dissect key features for the design of a potent and highly selective inhibitor of Human Pol-η (see publication list).
Results of research performed in the last years were also presented, with posters or as speaker, at several national and international conferences (CECAM, EMBO conferences, Gordon Conferences) on the topic.
1) Combination of classical and molecular modeling approaches to investigate the effect of antipsychotic drugs on cell proliferation kinetics.
Enrico Pieroni , Amit Kumar, Massimo Pisu, Vito Genna, Alessandro Concas and Giacomo Cao
Chemical Engineering Transactions, 2013, 32, 787-792.
2) Antigenic Peptide Molecular Recognition by DRB1 - DQB1 Haplotype modulates Multiple Sclerosis Susceptibility.
3) Functional motion of a key arginine and metal ions for DNA repair catalyzed by Y-family polymerases.
Vito Genna, Roberto Gaspari, Matteo Dal Peraro and Marco De Vivo
Nucleic Acids Res., 2016, 44, 2827-2836.
4) Self-Activated Mechanism for nucleic acid polymerization catayzed by DNA/RNA Polymerases.
Vito Genna, Pietro Vidossich, Emiliano Ippoliti, Paolo Carloni and Marco De Vivo.
J. Am. Chem. Soc., 2016, 138, 14592–14598.
5) First Principles Methods in Biology: From Continuum Models to Hybrid Ab Initio Quantum Mechanics/Molecular Mechanics in Simulating Enzyme Reactivity: Computational Methods in Enzyme Cataysis (Chapter 9)
Jens Dreyer, Giuseppe Brancato, Emiliano Ippoliti, Vito Genna, Marco De Vivo, Paolo Carloni, Ursula Rothlisberger.
Ed. Iñaki Tuñón and Vicente Moliner, Royal Society of Chemistry, 2016, 294-339.
6) Newly-identified catalytic elements expand the two-metal-ion architecture of DNA and RNA processing enzymes.
Vito Genna*, Matteo Colombo*, Marco Marcia and Marco De Vivo.
Manuscript submitted for publication.
- Core-Hours Grant. John von Neumann Institute for Computing (NIC) John von Neumann Institute for Computing (NIC) granted 300,000 core-h on JUROPA supercomputer at the Jülich Supercomputing Centre (JSC) for the project "Mechanism and Energetics of the nucleotidyl-transfer Reaction Catalyzed by DNA Polymerases."
Vito Genna, Dr. Emiliano Ippoliti, Dr. Pietro Vidossich, Prof. Dr. Paolo Carloni and Dr. Marco De Vivo.
- Marco Polo Fellowship, 2014. Alma Mater Studiorum - Università di Bologna -
- COVER article. Molecular BioSystems Journal, Royal Society of Chemistry. DOI: 10.1039/C4MB00203B
- Prize. Best student in Cellular and Molecular Biology in 2013. Università degli Studi di Cagliari, Italy.