Seminars at the Faculty of Informatics

Speaker: Giorgio Colombo
  Consiglio Nazionale delle Ricerche, Italy
Date: Thursday, May 12, 2016
Place: USI Lugano Campus, room SI-008, Informatics building (via G. Buffi 13)
Time: 15:30

 

Abstract:

In this seminar, I will present recent our results on the development of computational strategies for the discovery of new modulators of protein-protein interactions with drug-like properties and for the design of epitopes starting from the structures of protein antigens.

In the first part, we will present novel methods of computational analysis of signal propagation mechanisms and communication pathways in proteins. The analysis is carried out using molecular dynamics (MD) simulations, combined with a signal propagation model. We elucidate the mechanisms of signal propagation and determine hot spot residues involved in the regulation of the functionally oriented aspects of protein conformational dynamics. Interestingly, we find that different communication mechanisms are triggered by different ligands. This information is then used to design and synthesize new allosteric modulators of the internal dynamics as well as the interactions properties of the targeted proteins. The activities of the modulators are tested in various models in vitro and in vivo.

In the second part, we discuss new methods to investigate the role of sequence and structures in determining the interaction properties of proteins and domains. In particular, we focus on the prediction of antibody-binding sites: Epitope prediction has in fact proven challenging. The antibody binding properties of an antigen depend on its structure and related dynamics. To this end, we have developed an integrated analysis of the dynamical and energetic properties of antigens, to identify non-optimized, low-intensity energetic interaction-networks in the protein structure isolated in solution. The method is based on the idea that recognition sites may correspond to localized regions with low-intensity energetic couplings with the rest of the protein allowing them to undergo conformational changes, to be recognized by a binding partner and to tolerate mutations with minimal energetic expense. Analyzing the results on isolated proteins and benchmarking against antibody-complexes, the method successfully identifies binding sites located on the protein surface and accessible by putative binding partners. The combination of dynamics and energetics can thus discriminate between epitopes and other substructures based only on physical properties.

Next, we test our predictions on a series of antigens from B.pseudomallei, a Gram-negative bacterium responsible for melioidosis, a serious and often fatal infectious disease that is poorly controlled by existing treatments. Predicted epitopes are engineered as synthetic peptides and shown to be selectively immunorecognized to the same extent as recombinant proteins in sera from melioidosis-affected subjects. Moreover, antibodies raised against designed sequences prove to be bactericidal.

Finally we will discuss the implication of these methods in drug and vaccine discovery.

 

Biography:

Giorgio Colombo (born 24th June 1971) received his M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, he continued his studies obtaining a Ph.D. in chemical sciences from the University of Milano in 2000. During the Ph.D period he 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. He then moved to the University of Groningen as a postdoc with profs. H. Berendsen and A. Mark to work on the molecular dynamics simulations of the folding and stability of proteins and peptides.

Dr. Giorgio Colombo joined the Institute for Molecular Recognition Chemistry, Italian National Research Council, in 2001 where he is currently head of the biocomputing group. Currently his research focuses on the development of new cancer therapeutics for the inhibition and regulation of Hsp90 pathways and new antiangiogenic and vascular agents targeting FGF2. In recent years, the he has developed and validated methods for drug design, allosteric site identification and development of allosteric inhibitors of Hsp90, for the study of the correlation between mutations and drug resistance, analysis of protein stability/flexibility and drug-receptor interactions. Part of his activities has been dedicated to the study of protein/protein and protein/antibody interactions and to the design of molecules with immunological activities in the context of structural vaccinology. He is author or coauthor of more than 130 scientific publications, all on international journals, with an overall H-index of 33 (Google Scholar). He has received the National Habilitation (Abilitazione Scientifica Nazionale) for Full Professor(Professore Ordinario, Prima Fascia) in Organic Chemistry (03/C1), Physical Chemistry (03/A2), Biochemistry (05/E1)

 

Host: Prof. Vittorio Limongelli