title: Allosteric Modulation of Alpha7 Nicotinic Receptors: Mechanistic Insight through Metadynamics and Essential Dynamics.
abstract: Increasing attention has recently been devoted to allosteric modulators, as they can provide inherent advantages over classic receptor agonists. In the field of nicotinic receptors (nAChRs), the main advantage is that allosteric modulators can trigger pharmacological responses, limiting receptor desensitization. Most of the known allosteric ligands are "positive allosteric modulators" (PAMs), which increase both sensitivity to receptor agonists and current amplitude. Intriguingly, some allosteric modulators are also able to activate the α7 receptor (α7-nAChR) even in the absence of orthosteric agonists. These compounds have been named "ago-allosteric modulators" and GAT107 has been studied in depth because of its unique mechanism of action. We here investigate by molecular dynamics simulations, metadynamics, and essential dynamics the activation mechanism of α7-nAChR, in the presence of different nicotinic modulators. We determine the free energy profiles associated with the closed-to-open motion of the loop C, and we highlight mechanistic differences observed in the presence of different modulators. In particular, we demonstrate that GAT107 triggers conformational motions and cross-talk similar to those observed when the α7-nACh receptor is in complex with both an agonist and an allosteric modulator.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.affiliation: Institute of Research in Biomedicine (IRB) , Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Capelli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.affiliation: Drug Discovery and Development-Computation, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genoa, Italy.|Department of Pharmacy and Biotecnology, University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D008024:Ligands; D064569:alpha7 Nicotinic Acetylcholine Receptor