EVOLUTION OF METABOLISM

前列腺素H2合成酶-1(PGHS-1)催化 必需脂肪酸花生四烯酸(AA)转化为 前列腺素H2[17]。阿司匹林、氟比洛芬和其他非类固醇 抗炎药物直接靶向PGHS-1并抑制第一种 通过阻止AA访问 环氧合酶活性部位。根据PGHS-1的晶体结构， 在活性部位结合氟比洛芬的情况下，AA模型嵌入 这种酶已经被提出，其中AA取代了抑制剂 [18]。这项研究的目的是阐明AA的折叠 进入环氧合酶的狭长疏水结合通道 位点，并确定指导AA结合的关键残基。掌舵 分子动力学计算(SMD)[3-8,103,104] 对PGHS-1的一个单体(9000个原子)进行解结合 高-二聚体，其推测的环氧合位置结合了AA， 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，每个键相连 另一种是通过一对构象柔性的单键。这个 解绑机构可以被描述为一系列的旋转 这些单键留下了脂肪酸的“刚性主干” 由构象不灵活的顺式双键相对形成 不受影响。我们的假设是，这种协调运动是 为AA的化学结构所特有，对 绑定和识别机制。另一组模拟是 使用目标分子动力学(TMD)方法进行[105]。 SMD和TMD模拟的比较表明，这些路径 这两种方法生成的数据显示出非常相似的协同模式 AA解键过程中围绕单键的转动。

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.