Abstract
We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.
Highlights
Histamine is an important mediator and neurotransmitter that is involved in a broad spectrum of central and peripheral physiological as well as pathophysiological processes, such as allergies and inflammation
Histamine receptors are 7-transmembrane receptors, which belong to the family of G-protein coupled receptors (GPCR), a very common target for a wide range of therapeutics used in modern pharmacotherapy, and differ in receptor distribution, ligand binding properties, signaling pathways and functions
The shape of the RDF curve and a slightly lower distance for the peak maximum for N2 (2.8 Å relative to 2.9 Å for both N1 and N3), suggests that its interactions with the solvent molecules are stronger than with the other two nitrogen sites. This notion is found in excellent agreement with our earlier report [24], where we utilized the Car-Parrinello molecular dynamics simulation scheme to delineate the experimental IR spectra of histamine in water, which showed a broad feature between 3350 and 2300 cm−1 including a mixed contribution from the ring N3–H and the aminoethyl N2–H stretching vibrations, to indicate that the ring amino group absorbs at higher frequencies than the remaining three amino N2–H protons, implying the latter forms stronger hydrogen bonding with the surrounding waters
Summary
Histamine is an important mediator and neurotransmitter that is involved in a broad spectrum of central and peripheral physiological as well as pathophysiological processes, such as allergies and inflammation. Instead of utilizing chemical deuteration described earlier, in our preceding work [25], we have taken a different approach of introducing deuteration through the exchange mechanism by performing binding studies in pure D2 O In this way, we assured that all exchangeable hydrogen atoms, in both aqueous solution and within the H2 receptor will be replaced by deuterium, and that this will allow us to monitor how the hydrogen bonding interactions responsible for both the histamine hydration and its inclusion into the receptor binding site will be affected. While the in silico discrimination between agonists and antagonists, based on th
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