Istituto di Ricerca in Biomedicina
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Istituto di Ricerca in Biomedicina
Biologia Strutturale Computazionale
Panoramica
La nostra ricerca si concentra sulla comprensione di come sequenza, struttura e dinamica definiscano collettivamente la funzione delle biomolecole. Sfruttando tecniche avanzate come le simulazioni di dinamica molecolare e il machine learning, miriamo a colmare il divario tra strutture a livello molecolare e le loro implicazioni funzionali. Adottando un approccio interdisciplinare, attingiamo a principi e metodi della chimica, della fisica e della genetica per indagare le basi molecolari dei fenomeni biologici.
La nostra ricerca integra senza soluzione di continuità metodi computazionali (in silico) con approcci sperimentali (in vitro e in vivo), favorendo una prospettiva completa che ne aumenta la robustezza e l’applicabilità dei risultati. Nei prossimi anni, il nostro gruppo darà priorità allo sviluppo e al perfezionamento di metodi per modellare e prevedere con precisione le interazioni antigene-anticorpo.
Questo lavoro approfondirà la nostra comprensione delle risposte immunitarie alle infezioni e chiarirà i meccanismi alla base delle malattie autoimmuni. Attraverso questi sforzi, miriamo a contribuire alla progettazione di terapie innovative, inclusi vaccini di nuova generazione e trattamenti basati su anticorpi. In parallelo, stiamo ampliando i nostri framework computazionali per affrontare le sfide nella scoperta di farmaci a piccole molecole. Un focus centrale sarà identificare e progettare inibitori che modulino l’omeostasi proteica, un fattore chiave in malattie quali il cancro, l’amiloidosi e i disturbi neurodegenerativi. Integrando il design di farmaci basato sulla struttura e il machine learning, miriamo ad accelerare la scoperta di piccole molecole con effetti terapeutici precisi.
Questi inibitori non solo offrono promettenti soluzioni per il trattamento di malattie complesse, ma rappresentano anche una finestra sui meccanismi molecolari che guidano la progressione della malattia.
Combinando approcci computazionali innovativi con una rigorosa validazione sperimentale, aspiriamo ad avanzare la biologia strutturale e a tradurre i nostri risultati in applicazioni biomediche di impatto, contribuendo sia all’innovazione terapeutica che alla comprensione fondamentale della biologia.
Progetti
Researchers
Andrea Cavalli – Group Leader
Status: in progress
Overview
Alzheimer’s disease (AD) is recognized as the most spread neurodegenerative disease affecting over 30 million people worldwide. The development of the disorder has been linked to the presence of extracellular beta-amyloid (Ab) peptide aggregates of different sizes. Ab oligomeric species formed at early stages of the aggregation process are leading candicates for causing AD. Thus, targeting oligomers can be a very valuable strategy to combat Alzheimer’s disease. However, the molecular mechanism underlying the self-assembly of the different Ab species is not fully understood and it is not clear how the early soluble oligomeric species associate to form protofibrils and, subsequently, mature fibrils.
The main objective of this project is to apply computational techniques to elucidate small angle X-ray scattering (SAXS) data collected by our collaborators at University of Cambridge (Prof. M. Vendruscolo group) and resolve major coexisting components in Ab fibrillation process.
Researchers
Andrea Cavalli – Group Leader
Status: in progress
Overview
Light chain amyloidosis is a disorder associated with aggregation of immunoglobulin (Ig) light chains. Ig light chains with different sequences reveal varied amyloidogenic propensities and it is currently not clear which factors drive fibrillation process and, thus, cause pathological conditions.
In this project, we investigate a repertoire of toxic and non-toxic sequences and perform molecular dynamics simulation for selected light chain models with varied amyloidogenic propensities aiming at the elucidation of molecular determinants of light chain amyloidosis.
Researchers
Andrea Cavalli – Group Leader
Status: in progress
Overview
The process of how proteins reach their native basin of structures is poorly understood and constitutes an important problem in molecular biology. This process is called the protein folding problem, and is generally thought to proceed through large, concerted changes in structure.
In this project, we are studying the folding of two small proteins: the WW domain of Pin1 and Porcine peptide YY. These studies are carried out using molecular simulation combined with exact nuclear Overhauser enhancement data and/or chemical shift data obtained at multiple temperatures measured in the groups of collaborators Prof. Riek at the ETH in Zürich or Prof. Zerbe University of Zürich. Specifically, we are integrating all the experimental data with one simulation to obtain a full, thermodynamic and structural description of the protein folding process.
Researchers
Andrea Cavalli – Group Leader
Jacopo Sgrignani – Scientist
Status: in progress
Overview
Transcription factors (TFs) are central nodes in multiple oncogenic signalling pathways and represent attractive targets for development of novel cancer treatment strategies. However, very few direct pharmacological inhibitors of transcription factors are currently in the clinical trials. Signal Transducer and Activator of Transcription 3 (STAT3) belongs to the STAT family of transcription factors. As other STAT members, STAT3 is a cytoplasmic protein and is regulated by multiple post-transcriptional modifications (PTM), like phosphorylation, methylation and acetylation.
Increased expression and activity of STAT3 is very common in human cancers. STAT3 has a central role in critical signalling pathways for tumour initiation and progression. STAT3 drives tumour progression by promoting proliferation, survival, metabolic adaptation, tumour angiogenesis and immune tolerance and its downregulation by genetic or pharmacological means prevents or reverts tumorigenesis.
Many anticancer drugs inhibit upstream signaling pathways (e.g., JAK, EGFR) and affect STAT3 activation. In addition to these “indirect” inhibitors of the STAT3 pathway (e.g., JAK inhibitors), there is increasing interest in developing “direct” inhibitors of STAT3 that might interfere with the multiple diverse functions of this TF.
A number of small molecule compounds as well as natural products have been identified as direct STAT3 inhibitors (STAT3i). The aim of this study is to investigate the mechanism of action of a novel class of compounds with STAT3 inhibitory activity. In particular, we will study two compounds that interfere effectively with STAT3 and have potent anticancer activity in various tumor models. Experimental results suggest, that this new class of compounds acts by promoting the formation of large aggregates of STAT3 and that the formation of this aggregates is a direct consequence of conformational changes, disruption of specific inter-domain interactions and partial unfolding of STAT3 induced by STAT3i.
The objective of this study is the characterization of the mechanism of action of STAT3i at a molecular level. In particular we aim to:
Researchers
Andrea Cavalli – Group Leader
Status: in progress
Overview
Cyclophilins are a part of the ubiquitous family of enzymes which catalyses the isomerisation transition between peptidyl and prolyl conformations, which plays a crucial role in the folding of many proteins. However, these enzymes have also been identified as a putative drug-target to treat a number of diseases, including viral infections such as Hepatitis C.
In this project we wish to understand the molecular details of the catalysis of Cyclophilin A, and in particular also the inhibition of this function. To this end, we are collaborating with the group Prof. Riek at the ETH in Zürich to analyse high-resolution exact nuclear Overhauser enhancement data and residual dipolar coupling data on Cyclophilin A in complex with cyclosporin, which is known inhibitor of its function, and in absence of this inhibitor.
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