The clarification of the fundamental mechanisms responsible of gene expression and their therapeutic implications is of key urgency, given that ~8.2 million citizens die each year for cancer, and millions of people are affected by genetic diseases.

My research exploits advanced computational methods – based on Classical and Quantum Molecular Dynamics (MD), novel Cryo Electron Microscopy (CryoEM) refinement – and their integration with experiments to unravel the function and improve biological applications of key protein/nucleic acids complexes directly responsible of gene regulation, with important therapeutic applications for cancer treatment and genetic diseases.

Understanding CRISPR-Cas9 mechanistic function for improoved genome-editing 

cas9CRISPR-Cas9 has revolutionised life science toward a facile genome-editing technology, but the structural and mechanistic features underlying its function are unclear. Being fascinated by the ability of CRISPR to precisely manipulate nucleic acids, I have developed a research project for unravelling the mechanistic basis and improving biological applications of this unique genome-editing machinery. Supported by the long-standing experience in computational biophysics of Prof. J. Andrew McCammon (UCSD) and in close collaboration with Prof. M. Jinek (University of Zürich), I am applying advanced computational methods and exploiting the next-generation super computer ANTON-2 for capturing the mechanistic basis of CRISPR-Cas9. This will deliver fundamental information for the improvement and development of new and safer genome-editing technologies.

Read more: ACS Cent. Sci. 20162, 756–763

Exploring the therapeutic landscape of chromatin

UntitledIn the effort of expanding the therapeutic landscape of chromatin, as a collaboration between the Roethlisberger’s lab. (EPFL), Profs. P. J. Dyson and C. A. Davey (NTU-Singapore),  we studied novel metal-based chromatin binding agents, interfering with genome compaction and transcription. These compounds bind packed DNA and histones, being highly effective in cancer treatment.

Read more: Nat. Commun. 2017, 8, 14860.
Angew. Chem. Int. Ed. 2016, 55, pp 7441–7444
ChemMedChem. 2016, 11, pp 1199–1210

GroupII Intron: the ancestor of the human Spliceosome

RIBOZYME2RNA is a fundamental molecule that codes for protein and controls gene expression, playing a key regulation role in many cell responses and vital processes. From an original idea of Prof. A. Magistrato (SISSA) and in collaboration with the U. Roethlisberger (EPFL) lab, we shed light into the splicing mechanism, which is a key step in RNA maturation. We revealed a novel RNA-specific mechanism in GroupII intron, which is the ancestor of the huge macromolecular splicing machinery in humans: the Spliceosome. This finding suggests a novel functional path for the splicing mechanism in humans.

Read more: J. Am. Chem. Soc. 2016138, 10374–10377
J. Chem. Theory Comput., 201713, 340–352

Catalytic Metals and Enzymatic Processing of DNA & RNA

object012Several endonucleases cleave phosphodiester bonds of nucleic acids by exploiting a two-metal-ion aided mechanism (Steitz & Steitz, PNAS 1993, 90). As a collaborative effort between the IIT (De Vivo’s lab.) and EPFL (Dal Peraro lab.) we shed light on this fascinating mechanism via computational methods.

Read more: Acc. Chem. Res. 201548, pp 220–228
J. Chem. Theory Comput. 2013, 9, pp 857–862


            Graduate and master student projects

Anticancer Drug Discovery: Boosting Potency of Type II Topoisomerase PoisonsUntitled

By combining our computations with chemical synthesis and bio-assays (Prof. Sissi, Univ. of Padova), we proposed a rational for the anticancer activity of novel Topoisomerase II poisons that act as potent anticancer agents, causing cell death by trapping the covalent topoII-DNA cleavage complex during DNA topology modification.

Read more: Chem. Commun. 2015, 51, pp 14310-13

Mechanism of lipid selection and degradation

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My PhD has been devoted to the study of the Fatty Acid Amide Hydrolase (FAAH), a key membrane protein involved in the control of pain and pathophysiological processes like cancer and immune diseases. With this project, I earned experience in highly predictive computational approaches, such as free-energy methods and in-silico protein engineering. By integrating pharmacology (UC-Irvine), biochemistry (IIT) and molecular simulations (EPFLIIT), we have clarified the mechanisms of lipid selection and degradation in FAAH, with significant insights for novel drug-design efforts.

Read more: Eur. J. Med. Chem. 2015, 91, pp 15-26
J. Phys. Chem. B. 2015, 119, pp 789–801
J. Chem. Theory. Comput. 2013, 15, pp 1202-1213
J. Med. Chem. 2011, 54, pp 6612–6623

Density Functional Theory (DFT) for Solar Cells technologyobject018

Solar cells are the energy revolution of the 21th century, converting solar energy in electricity. In close collaboration with Prof. M. Graetzel (EPFL), who pioneered solar cells technology, we employed Density Functional Theory for characterizing the atomistic and electronic structure nature of hybrid organic-inorganic perovskites, which are novel effective materials used for solar cells technology. Our outcomes have been directly exploited in the Graetzel lab. for developing more efficient solar cells technologies.

Read more: J. Mater. Chem. A. 2016, 4, pp 15997-16002. 

A duel with pain: multi-target drug discovery

UntitledMulti-target drug discovery is promising for the development of innovative drugs. By applying molecular simulations and free energy methods, we have clarified the mechanism of action of ARN2508, a novel anti-inflammatory agent that inhibits both the Fatty Acid Amide Hydrolase (FAAH) and the cyclooxygenase (COX) enzymes. With this research, we provide the basis of dual inhibition for anti-inflammatory treatments. 

Read more: ChemMedChem 2016, 11, pp 1252 –1258

Structural elucidation of organic compounds

UntitledMy early work has been focused on the development of prediction methods, based on the first Karplus and Altona models, aimed at predicting NMR coupling constants (3JC-H), which are of key importance for the structural elucidation of bioorganic and pharmaceutically relevant compounds. Based on Density Functional Theory calculations, I have formally derived a general 3JC-H prediction equation, which is successfully used as a support to NMR experiments for the structural elucidation of organic compounds.

Read more: J. Org. Chem., 201075, pp 1982–1991