Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, 1111, Budapest Műegyetem rakpart 3., Hungary.
Department of Biotechnology, Faculty of Agriculture, Al-Azhar University, Cairo, 11651, Egypt.
Chemistry. 2022 Sep 1;28(49):e202200930. doi: 10.1002/chem.202200930. Epub 2022 Jul 11.
The binding of small gas molecules such as NO and CO plays a major role in the signaling routes of the human body. The sole NO-receptor in humans is soluble guanylyl cyclase (sGC) - a histidine-ligated heme protein, which, upon NO binding, activates a downstream signaling cascade. Impairment of NO-signaling is linked, among others, to cardiovascular and inflammatory diseases. In the present work, we use a combination of theoretical tools such as MD simulations, high-level quantum chemical calculations and hybrid QM/MM methods to address various aspects of NO binding and to elucidate the most likely reaction paths and the potential intermediates of the reaction. As a model system, the H-NOX protein from Shewanella oneidensis (So H-NOX) homologous to the NO-binding domain of sGC is used. The signaling route is predicted to involve NO binding to form a six-coordinate intermediate heme-NO complex, followed by relatively facile His decoordination yielding a five-coordinate adduct with NO on the distal side with possible isomerization to the proximal side through binding of a second NO and release of the first one. MD simulations show that the His sidechain can quite easily rotate outward into solvent, with this motion being accompanied in our simulations by shifts in helix positions that are consistent with this decoordination leading to significant conformational change in the protein.
小分子气体分子（如 NO 和 CO）的结合在人体信号通路中起着重要作用。人类唯一的 NO 受体是可溶性鸟苷酸环化酶（sGC）-一种组氨酸配位的血红素蛋白，它在结合 NO 后，激活下游信号级联反应。NO 信号转导的损害与心血管和炎症性疾病等有关。在本工作中，我们使用了一系列理论工具，如 MD 模拟、高级量子化学计算和混合 QM/MM 方法，来研究 NO 结合的各个方面，并阐明最可能的反应路径和反应的潜在中间体。作为模型系统，使用了与 sGC 的 NO 结合域同源的 Shewanella oneidensis（So H-NOX）中的 H-NOX 蛋白。预测信号通路涉及到 NO 的结合，形成六配位的中间血红素-NO 络合物，随后相对容易地发生 His 配位，形成具有 NO 的五配位加合物，NO 位于远端，可能通过第二个 NO 的结合和第一个 NO 的释放发生异构化到近端。MD 模拟表明 His 侧链可以很容易地向外旋转进入溶剂，在我们的模拟中，这一运动伴随着螺旋位置的变化，这与配位导致蛋白质发生显著构象变化是一致的。
