Project description DEENESFRITPL Novel computational methods for molecular binding studies The predictive power of computation remains low in studies of molecular binding interactions mainly due to the poor correlation of in silico models with the real world. This is the case in drug discovery where the in vivo drug efficacy’s correlation with ligand residence time fails to be predicted by current computational methods. The EU-funded CoMMBi project aims to reshape state-of-the-art computation in molecular binding. The project will develop and apply cutting-edge computational techniques based on free-energy calculations, machine learning and multiscale molecular dynamics simulations. The predictive power of the developed approaches will be tested by elucidating the functional mechanisms of the G-protein coupled receptors, pharmacologically important membrane proteins targeted by many marketed drugs. Show the project objective Hide the project objective Objective Molecular binding is a major research topic that has undoubtedly benefited of recent technological innovation, especially in the area of the so-called computational sciences. However, the predictive power of computations remains low mainly due to the poor correlation of the in-silico models with the real world. A clear example is drug discovery where the drug in vivo efficacy is seen correlated to the ligand residence time, which is hardly predictable by current computational methods. The present proposal tackles the challenge aiming at reshaping the border of the state-of-the-art simulations in molecular binding. I outline a research program that realises a vision where drug design is entrusted to ligand binding affinity and kinetics prediction, and molecular binding interactions are simulated in a realistic plasma membrane model. To achieve the ambitious goals of the research, my team will develop and apply cutting-edge computational techniques based on free-energy calculations, machine learning and multiscale molecular dynamics simulations. Evidence of the innovative nature of the developed approaches will be given by elucidating fundamental aspects of the functional mechanism of the G-protein coupled receptors (GPCRs), a pharmacologically prominent membrane protein family targeted by ~ 40% of marketed drugs. We will achieve a thorough characterization of the binding thermodynamics and kinetics of signal molecules (antagonists and agonists) that will be used by an original machine learning model to identify novel receptor antagonists with prescribed binding affinity and residence time. We will then investigate the receptor conformational transition from the inactive to the active state and develop an ad hoc multiscale approach to characterize the formation of GPCRs dimers, oligomers and clusters in cell membrane and their interaction with the G-protein that activates the signal transduction. Experiments will be performed to validate all the in-silico results. Fields of science natural sciencesphysical sciencesthermodynamicsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesopticsmicroscopynatural sciencescomputer and information sciencescomputational sciencenatural sciencescomputer and information sciencesartificial intelligencemachine learning Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-COG - ERC CONSOLIDATOR GRANTS Call for proposal ERC-2020-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution UNIVERSITA DELLA SVIZZERA ITALIANA Net EU contribution € 1 999 497,00 Address VIA GIUSEPPE BUFFI 13 6900 Lugano Switzerland See on map Region Schweiz/Suisse/Svizzera Ticino Ticino Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 497,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITA DELLA SVIZZERA ITALIANA Switzerland Net EU contribution € 1 999 497,00 Address VIA GIUSEPPE BUFFI 13 6900 Lugano See on map Region Schweiz/Suisse/Svizzera Ticino Ticino Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 497,00
