Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, HR-10000 Zagreb, Croatia.
Laboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, SI-1001 Ljubljana, Slovenia.
Molecules. 2020 Dec 18;25(24):6017. doi: 10.3390/molecules25246017.
We used a range of computational techniques to reveal an increased histamine affinity for its H 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 closely matching the experimental value of -5.9 kcal mol. 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 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, being in excellent agreement with an experimental value of -0.75 kcal mol, thus confirming the relevance of hydrogen bonding for the H receptor activation.
我们使用了一系列计算技术来揭示氘代后组胺与其 H 受体的亲和力增加，这可以通过受体内部和结合前水相中的氢键相互作用的改变来解释。分子对接确定了第三和第五跨膜α-螺旋之间的区域为几个组胺构象的可能结合口袋，最有利的结合能为-7.4 kcal/mol，与实验值-5.9 kcal/mol 非常接近。随后的分子动力学模拟和 MM-GBSA 分析将 Asp98 识别为最主要的残基，占总结合能的 40%，通过与组胺-NH 基团的持续氢键形成，后者通过与 Tyr250 的 N-H∙∙∙O 氢键进一步固定。与早期文献的提议不同， Thr190 通过其-OH 基团在氢键中没有明显的重要作用，而是在 C-H∙∙∙π 与咪唑环的接触中，而其前一部分则不断与 Asp186 形成氢键。最后，在受体簇模型内进行量子化学计算并利用可离解 X-H 键（X = N、O、S）的经验量化，支持氘代诱导的亲和力增加，计算得到的结合自由能差异为-0.85 kcal/mol，与实验值-0.75 kcal/mol 非常吻合，从而证实了氢键对 H 受体激活的相关性。
