Understanding function of G-Protein Coupled Receptors by atomistic and multiscale simulations
CECAM-Lugano, Lugano, Switzerland
G-protein coupled receptors (GPCRs) are membrane proteins responsible for the transduction of a wide range of signals across the plasma membrane, regulating several vital functions through their activation or deactivation by endogenous and exogenous ligands. [1,2]. These include metabolism, immune and inflammatory response, growth and differentiation, neurotransmission, olfaction, and vision, among many others. It is therefore not surprising that GPCRs are the targets of ∼50% of prescribed drugs (and 25 of the 100 top-selling) and are the most important target of current pharmaceutical development .
Despite the efforts and the progress made in recent years, a comprehensive characterisation of GPCR function is still lacking. This is because signaling mechanisms of membrane receptors involve subtle conformational changes. Moreover, the complexity of their native environment and the inherently dynamical nature of these transitions make their in-depth investigation via experimental techniques difficult. As such, the use of molecular dynamics (MD) simulations represents a natural choice for the study of these functional motions [4,5], providing an atomistic description of the interactions at work. The prospective impact is increased significantly by the publication of hundreds of GPCR structures in the past 15 years, bound to ligands of all activities and several very recent structures co-crystallized with G-proteins.
Comparison of active and inactive structures for several GPCRS suggested that binding of an agonist molecule to the extracellular orthosteric site causes an outward motion of the cytoplasmic part of transmembrane helix 5 (TM5) and 6 (TM6) [6-10]. Computational investigations not only confirmed this model , but revealed additional details about how the binding of agonists and G protein subunits influence the dynamics of GPCR molecule by reducing the flexibility of their extracellular (EC) and intracellular (IC) regions . Some attempts were made to compute the energy landscape of GPCR activation starting from the inactive, unbound conformation in the absence of G-protein, to the active, bound one in presence of the alpha-, beta- and gamma-subunits, in both the open and closed states . However, due to the timescale of these transitions and the magnitude of the systems at hand, such calculations are particularly demanding in terms of computational resources. The functional mechanisms involved in GPCR activation, such as ligand binding/unbinding and large-scale receptor motions occur on msec timescales and remain inaccessible through standard simulations. These limitations can be overcome by employing enhanced sampling methods, like umbrella sampling  and metadynamics [15-17], coarse-grained modelling,  or multiscale approaches .
Much work remains to be done in the application of advanced simulation methods to GPCRs, motivating the present conference proposal. Major open questions include functional GPCR dimers, how the lipid environment influences GPCR function, the allosteric mechanism by which ligand binding at the GPCR activates the G-protein, and coupling of GPCRs to non G-protein signaling pathways. [20-25], [21-28]. Constantly improving hardware solutions are opening new opportunities, providing the technical edge needed for simulating realistic membrane models that may improve our understanding of the role of specific lipid / protein interactions , therefore paving the way toward a new era of MD calculations in quasi-physiological conditions.
As such, the GPCR field is a rapidly progressing and highly appealing area of interest that encompasses several branches of science: from pharmacology to biology, chemistry, physics and medicine. One would expect that such a broad range of expertise is reflected upon the nature of the workshops yearly organised on this topic. Indeed, there is quite a number of events dedicated to experimental studies, whereas computational ones are scarce, if anything. Therefore, we deem that a GPCR-themed workshop would be of great interest to the scientific community and it would be a powerful addition to the CECAM programme, as also proved by our starred list of confirmed speakers including a Nobel prize laureate. This workshop will bring together a diverse group of simulation and experimental experts (with particular focus on students and early stage investigators) to establish a positive and productive exchange on the new challenges posed by cutting-edge studies on ligand-GPCR binding mechanism and GPCR activation processes.
Paolo Conflitti ( Università della Svizzera Italiana ) - Organiser
Vittorio Limongelli ( USI Lugano / University of Naples ) - Organiser
Mark Sansom ( University of Oxford ) - Organiser
Edward Lyman ( University of Delaware ) - Organiser