Abstract
G-protein coupled receptors, the largest family of proteins in the human genome, are involved in many complex signal transduction pathways, typically activated by orthosteric ligand binding and subject to allosteric modulation. Dopaminergic receptors, belonging to the class A family of G-protein coupled receptors, are known to be modulated by sodium ions from an allosteric binding site, although the details of sodium effects on the receptor have not yet been described. In an effort to understand these effects, we performed microsecond scale all-atom molecular dynamics simulations on the dopaminergic D2 receptor, finding that sodium ions enter the receptor from the extracellular side and bind at a deep allosteric site (Asp2.50). Remarkably, the presence of a sodium ion at this allosteric site induces a conformational change of the rotamer toggle switch Trp6.48 which locks in a conformation identical to the one found in the partially inactive state of the crystallized human β2 adrenergic receptor. This study provides detailed quantitative information about binding of sodium ions in the D2 receptor and reports a possibly important sodium-induced conformational change for modulation of D2 receptor function.
Highlights
G-protein coupled receptors (GPCR) are highly sophisticated signal transduction machines able to respond to extracellular stimulus by activating diverse intracellular signaling pathways
The present work describes the application of long molecular dynamics (MD) simulations for exploring the effect of sodium ions in class A GPCRs and the mechanism involved in their role as allosteric modulators
In an effort to elucidate the mechanism of the sodium-induced effect, we have computationally investigated the mobility of sodium ions in the sodium-sensitive D2 receptor
Summary
G-protein coupled receptors (GPCR) are highly sophisticated signal transduction machines able to respond to extracellular stimulus by activating diverse intracellular signaling pathways Recent research in this field is unveiling the complexity of the mechanisms involved, which are far from being understood in detail. The experimental study of allosteric regulatory processes in GPCRs is difficult because contemporary techniques (X-ray crystallography [1,2,3,4,5], and FRET [6,7]) are unable to provide structural information of sufficient spatial resolution and time scales for describing specific atomic-level aspects of allosteric interactions In this scenario, computational methods like molecular dynamics (MD) simulation can be used to provide unique insight into some elusive aspects of the problem, by meeting the aforementioned requirements in terms of both spatial resolution and time scale needed. This analysis comprises a single 1.1 ms long simulation (MD1), one hundred 50 ns simulations (MD2) and biased metadynamics
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