Paper Citing NAMD - Abstract
Grazioso, Giovanni; Sgrignani, Jacopo; Capelli, Romina; Matera, Carlo; Dallanoce, Clelia; De Amici, Marco; Cavalli, Andrea
Allosteric Modulation of Alpha7 Nicotinic Receptors: Mechanistic Insight through Metadynamics and Essential Dynamics
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 55:2528-2539, DEC 2015
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 alpha 7 receptor (alpha 7-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 alpha 7-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 alpha 7-nACh receptor is in complex with both an agonist and an allosteric modulator.
