I was born in Correzzana (Italy) on June 24th 1971. I received my M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, I continued my studies obtaining a Ph.D. in chemical sciences from the University of Milano in 2000. During the Ph.D period, I spent one year as a visiting scientist in the laboratory of Prof. Ken Merz at the Pennsylvania State University, working on computational and theoretical approaches to study enzymatic and protein properties. I then moved to the University of Groningen as a postdoctoral fellow in the MD group headed by Profs. Herman Berendsen and Alan E. Mark to work on the molecular dynamics simulations of the folding and stability of proteins and peptides.
Next, I joined the Institute for Molecular Recognition Chemistry, Italian National Research Council, in 2001 where I founded and currently head of the biocomputing group.
In December 2017, I became a Full Professor of Organic Chemistry at the Dept. of Chemistry, University of Pavia. I have authored or coauthored more than 150 scientific publications, all on international journals.
RESEARCH INTERESTS
1. Computational Structural Pharmacogenomics-Dynamics Based Drug Design. Integrating molecular dynamics, computational physical-chemistry and bioinformatics approaches to study the dynamics and specificity of protein-protein, peptide-protein and protein-small molecule binding: translation of the information into pharmacophore models for drug design and screening is used to rationally design new molecules taking the full flexibility of the receptor and the ligand into account. Applications include the identification of new leads for the development of targeted cancer therapeutics for the inhibition of Hsp90 and FGF-2.
In this context, a significant effort in my research is devoted to the development of new computational/theoretical tools for the characterization of allosteric mechanisms in proteins and for the ab-initio prediction of possible allosteric binding sites. The broad objective is to identify the molecular effects of sequence-structure perturbation that are responsible for the modulation of the activity and recognition properties in proteins. These concepts are translated into new methods for the discovery of small molecule therapeutics for cancer.
2. Chaperone-Mediated Protein Folding Mechanisms. Protein Folding and Misfolding. Computer simulations and theoretical approaches to understand the mechanisms of coupling between binding and protein dynamics in chaperone mediated pathways. This entails mainly the analysis of local and global dynamics of Hsp90, analysis of Hsp90-protein recognition and binding. Despite being based on the specific case of Hsp90, the methods are fully general and are being applied to a variety of protein systems. In the folding field, we are active in the development of atomic-resolution physics based models for the all-atom prediction of protein structure and (mis)folding mechanisms from sequence information. The models shed light on the effects of (genetic) mutations on the structural and aggregation properties of sequences.
3. Prediction of the Structural Determinants of Protein-Antibody and Protein-Protein Interactions. Current data accumulating from reverse vaccinology studies show that only a small fraction of surface-exposed proteins appears to elicit antibodies with bactericidal activity. By using information generated by reverse vaccinology projects we are developing and applying a novel integrated approach to single out the structural requirements for viable bactericidal vaccine candidates, and will develop bioinformatics tools to predict compliance with such structural requirements. To this end, a systematic analysis of sequence, structure, dynamics and interactions of selected protein targets is undertaken. New protein-interaction prediction methods based only on structural and energetic information have been developed for the particular case of Protein-Antibody recognition. The methods are being further developed into general predictors of protein-protein interactions.
MAIN GRANTS
– Coordinator of the “Young Investigator Project” of the Ministry of health (2009-2012; 500K€): “Combining biophysics, bioinformatics and chemical biology for the discovery of the new antineoplastic molecules based on endogenous inhibitors of angiogenesis”;
– PERSONAL AWARD FROM THE CARIPLO-UNESCO CALL “Exploration of new research frontiers – Award 2011”. Title of the project: Chemical control of signalling pathways by modulation of hub proteins (Checosp), 230000€. The selection committee was composed by: – Aaron Ciechanover, Technion- Israel Institute of Technology, Nobel Laureate for Chemistry 2004; – Gerhard Ertl, Fritz-Haber Institut Max-Planck, Nobel Laureate for Chemistry 2007 – Oliver Guthmann, Investment Manager of BASF Venture – Krzysztof Matyjaszewski, Carnegie Mellon University, Wolf Prize for Chemistry 2011- Phillip Szuromi, Supervisor Senior Editor of Science Magazine
– PI of the project: “Discovery of selective modulators of the functional dynamics of Hsp90 family members as novel anticancer compounds.” Italian Association for Cancer Research (AIRC), 2015-2018, 296000€
AWARDS
Elected member to the executive board of the “Division of Biological Chemistry” of the Italian Chemical Society
Recipient of the Young Investigator Award from the “Division of Biological Chemistry” of the Italian Chemical Society in 2004
Recipient of a Marie Curie Fellowship in the year 2000
REPRESENTATIVE PUBLICATIONS (last 5 years)
-Sattin, S.; Tao, J.; …., Colombo, G. Activation of Hsp90 enzymatic activity and conformational dynamics through rationally designed allosteric ligands. Chemistry – A European Journal 2015, 21(39), 13598-608.
– Ronca, R.; Giacomini, A.; Di Salle, E.; Coltrini, D.; Pagano, K.; Ragona, L.; Matarazzo, S.; Rezzola, S.; Maiolo, D.; Torella, R.; Moroni, E.; Mazzieri, R.; Escobar, G.; Mor, M.; Colombo, G.*; Presta, M. A long-pentraxin 3 derivative as the first small molecule FGF-Trap for cancer therapy. Cancer Cell 2015, 28(2), 225-239
– Moroni, E.; Zhao, H.; Blagg, B.S.J.; Colombo, G. Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities. Journal of Chemical Information and Modeling 2014, 54(1), 195-208
– Gourlay, L.J.; Peri, C.; …. Colombo, G.; Bolognesi, M. Exploiting the Burkholderia pseudomallei Acute Phase Antigen BPSL2765 for Structure-Based Epitope Discovery/Design in Structural Vaccinology. Chem Biol 2013, 20(9), 1147-1156. Highlighted in Chem Biol by R. Rappuoli.
– Peri, C.; Gagni, P.; Combi, F.; Gori, A.; Chiari, M.; Longhi, R.; Cretich, M.; Colombo, G. Rational epitope design for protein targeting. ACS Chemical Biology 2013, 8(2), 397-404
– Morra, G.; Potestio, R.; Micheletti, C.; Colombo, G. Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations. PLoS Comp. Biol. 2012, 8(3): e1002433
– Morra, G.; Neves, M.A.C.; Plescia, C.J.; Tsutsumi, S.; Neckers, L.; Verkhivker, G.; Altieri, D.C.; Colombo, G. Dynamics-Based Discovery of Allosteric Inhibitors: Selection of New Ligands for the C-terminal Domain of Hsp90. Journal of Chemical Theory and Computation 2010, 6:2978-2989
the colombo lab 