Binding of histamine to the G-protein coupled histamine H1 receptor plays an important role in the context of allergic reactions; however, no crystal structure of the resulting complex is available yet. To deduce the histamine binding site, we performed unbiased molecular dynamics (MD) simulations on a microsecond time scale, which allowed to monitor one binding event, in which particularly the residues of the extracellular loop 2 were involved in the initial recognition process. The final histamine binding pose in the orthosteric pocket is characterized by interactions with Asp1073.32, Tyr1083.33, Thr1945.43, Asn1985.46, Trp4286.48, Tyr4316.51, Phe4326.52, and Phe4356.55, which is in agreement with existing mutational data. The conformational stability of the obtained complex structure was subsequently confirmed in 2 μs equilibrium MD simulations, and a metadynamics simulation proved that the detected binding site represents an energy minimum. A complementary investigation of a D107A mutant, which has experimentally been shown to abolish ligand binding, revealed that this exchange results in a significantly weaker interaction and enhanced ligand dynamics. This finding underlines the importance of the electrostatic interaction between the histamine ammonium group and the side chain of Asp1073.32 for histamine binding.
Keywords: Allergic reactions; G-protein coupled receptors (GPCRs); Histamine; Ligand binding; Metadynamics; Molecular dynamics simulations; Receptor–ligand interactions.