EVOLUTION OF METABOLISM

前列腺素H2合酶-1（PGHS-1）催化前列腺素H2的合成。 将必需脂肪酸花生四烯酸（AA）转化为 前列腺素H2 [17]。 阿司匹林、氟比洛芬和其他非甾体 抗炎药直接靶向PGHS-1， 通过防止AA进入其转变的步骤， 环氧合酶活性位点。 基于PGHS-1的晶体结构， 与氟比洛芬结合在活性位点，AA嵌入模型， 有人建议用AA代替抑制剂 [18]第10段。 研究的目的是阐明AA的折叠 进入环氧合酶狭窄的疏水结合通道 位点，并鉴定引导AA结合的关键残基。 转向 分子动力学计算（SMD）[3 - 8，103，104] 在PGHS-1的一个单体（9，000个原子）上进行解结合 AA结合在其推定的环氧化位点的同源二聚体， 导致配体从其狭窄的疏水结合中退出 频道 *。 AA含有四个刚性顺式双键， 另一个是通过一对构象柔性单键。 的 解绑机制可以被描述为一系列的旋转， 这些单键离开脂肪酸的"刚性骨架"， 由构象上不灵活的顺式双键形成， 不受影响 我们的假设是，这种类型的协同运动是 特定于AA的化学结构，并且对于 结合和识别机制。 另一组模拟是 用靶向分子动力学（TMD）方法进行[105]。 SMD和TMD模拟的比较显示， 这两种方法产生的结果显示出非常相似的协同模式， 在AA解键期间围绕单键旋转。

The enzyme prostaglandin H2 synthase-1 (PGHS-1) catalyzes the transformation of the essential fatty acid, arachidonic acid (AA), to prostaglandin H2 [17]. Aspirin, flurbiprofen, and other non-steroidal anti-inflammatory drugs directly target PGHS-1 and inhibit the first step of its transformation by preventing access of AA to the cyclooxygenase active site. Based on the crystal structure of PGHS-1, with flurbiprofen bound at the active site, a model for AA embedded in the enzyme has been suggested, in which AA replaces the inhibitor [18]. The aim of the investigation is to elucidate the folding of AA into the narrow hydrophobic binding channel of the cyclooxygenase site, and to identify key residues guiding AA binding. Steered Molecular Dynamics calculations (SMD) [3-8, 103, 104] of enforced unbinding were carried out on one monomer (9,000 atoms) of the PGHS-1 homo-dimer with AA bound in its putative cyclooxygenation site, leading to the exit of the ligand from its narrow hydrophobic binding channel*. AA contains four rigid cis double bonds connected to each other by a pair of conformationally flexible single bonds. The unbinding mechanism can be described as a series of rotations around these single bonds that leave the "rigid backbone" of the fatty acid formed by the conformationally inflexible cis double bonds relatively unaffected. Our hypothesis is that this type of concerted motion is specific for the chemical structure of AA and is important for the binding and recognition mechanism. Another set of simulations was carried out with the Targeted Molecular Dynamics (TMD) method [105]. A comparison of the SMD and TMD simulations revealed that the pathways generated by both methods show very similar modes of concerted rotations around single bonds during the unbinding of AA.