Insight into G Protein-Coupled Receptors through Molecular Dynamics Simulations

In recent decades, technological advancement has been increasing extremely rapidly and this allowed to open the way to wide computational approaches able to guide and support the experimental work of biological sciences. Currently, it is possible to model the behaviour of chemical systems and reach the atomistic scale. From this point of view, the ability to understand how a ligand (small molecule or peptide) interacts with its biological target and through which mechanism the allosteric and orthosteric binding sites crosstalk may lead to the development of the high efficacy therapeutic agents that may avoid negative side effects. Among the available computational techniques, molecular dynamics (MD) contributes significantly to the understanding of protein-drug recognition, providing detailed information on structural flexibility and conformational changes, the supervised molecular dynamics(SuMD) allows to understand the (un)binding paths differences, and metadynamics (MetaD) enhances the number of the states explored. These techniques were employed in this PhD thesis to study G protein-coupled receptors (GPCRs),one of the largest families of proteins in the mammalian genome. In particular two receptors have been analysed: free fatty acid receptor 1 (FFAR1) and calcitonin receptor (CTR), respectively belonging to class A and class B of GPCRs. The results highlight that allosterism is a crucial event for the activation mechanism whether exerted by a molecule (such as AP8 for FFAR1) or by an accessory protein (such as RAMP for CTR).