The understanding of the fundamental mechanisms responsible of gene expression and of their therapeutic implications is of key urgency, given an ever-increasing incidence of genetic diseases and of cancer in the world.

My research is focused on the application of advanced computational methods – including all-atom Molecular DynamicsQuantum-based and novel Cryo Electron Microscopy refinement methods – and of their integration with experiments to unravel the function and improve applications of key macromolecular assemblies involved in DNA cleavage and replication, RNA transcription and translation, with important therapeutic applications for the treatment of cancer and genetic diseases.

CRISPR-Cas9: mechanistic understanding and rational design 


CRISPR-Cas9 is a transformative genome editing technology, but the structural and mechanistic features underlying its function are unclear. My research aims at unravelling the mechanistic basis and at improving biological applications of this unique genome-editing machinery. I am applying advanced computational methods and using the next-generation supercomputer ANTON-2 for the mechanistic understanding and rational design of CRISPR-Cas9. This research will be fully integrated with experiments, leading to the design of novel genome editing tools with improved specificity and controllable activity.

Collaborators: Prof. Martin Jinek (University of Zürich), Prof. Victor S. Batista (YALE)

Read more: J. Am. Chem. Soc. 2017, in press
Proc. Natl. Acad. Sci. USA, 2017, 114, pp. 7260–7265. 
ACS Cent. Sci. 20162, pp. 756–763.

Nucleosome dynamics and chromatin drug development


Double-stranded – or “naked” – DNA  is assumed to be the main biological target of metal drugs, but DNA packed in chromatin can also act as as binding partner, offering alternative routes for drug discovering. I have clarified the mechanism of action of novel metal-based anticancer agents, which interfere with transcription, deciphering their target preference and the corresponding relationships to cytotoxicity and impact on cancer cell function.

Collaborators: Prof. Paul J. Dyson (EPFL) and Prof. Curtis A. Davey (NTU-Singapore)

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

Dissecting the mechanistic basis of non-coding RNA

RNA is a fundamental molecule that codes for protein and controls gene expression, playing a key regulation role in many cell responses and vital processes, such as human genetic heritance and diseases. I am interested in clarifying the molecular basis of non-coding RNA, which regulates gene expression via a variety of yet unknown mechanisms. We have suggested a mechanism for the splicing reaction in the bacterial groupII intron, paving the way for the mechanistic study of the human Splicesome.

Collaborators: Prof. A. Magistrato (SISSA)

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

Catalytic Metals and Enzymatic Processing of DNA & RNA

As originally revealed by Steitz & Steitz (PNAS 1993, 90), DNA/RNA endonucleases perform phosphodiester bond cleavage via a two-metal-ion aided mechanism. I am using computational methods to clarify the two-metal aided mechanism in several endonucleases, including my recent work on CRISPR-Cas9. My interest in understanding the Steitz & Steitz mechanism has started as a graduate student, when I pursued studies on typeII topoisomerase and other endonucleases.

Collaborators: Prof. Dal Peraro (EPFL).

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