Positively Charged Residues in the Head Domain of P2X4 Receptors Assist the Binding of ATP

Abstract

P2X receptors are a family of trimeric cationic channels located in the membrane of mammalian cells. They open in response to the binding of ATP. The differences between the closed and open structures have been described in detail for some members of the family. However, the order in which the conformational changes take place as ATP enters the binding cleft, and the residues involved in the intermediate stages, are still unknown. Here, we present the results of umbrella sampling simulations aimed to elucidate the sequence of conformational changes that occur during the reversible binding of ATP to the P2X4 receptor. The simulations also provided information about the interactions that develop in the course of the process. In particular, they revealed the existence of a metastable state which assists the binding. This state is stabilized by positively charged residues located in the head domain of the receptor. Based on these findings, we propose a novel mechanism for the capture of ATP by P2X4 receptors.

Outlook on the Development and Application of Molecular Simulations in Latin America

“…MD simulations proved to be one of the most popular computational chemistry tools. In this special issue, atomistic MD simulations have been applied in many studies to understand key structural and functional properties of proteins, − receptor activation, insights into the binding of ligands, − mutations, ,− protein folding, and inhibitor design . In addition, combined free energy simulations and NMR chemical-shift perturbation has been utilized to identify transient cation-π contacts in proteins .…”