Abstract
We used a range of computational techniques to reveal an increased histamine affinity for its H(2) 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 -NH(3)(+) 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 H(2) receptor activation.