Molecular dynamics simulations of arachidonic acid complexes with COX-1 andCOX-2: Insights into equilibrium behavior
Molecular dynamics simulations of arachidonic acid complexes with COX-1 andCOX-2: Insights into equilibrium behavior
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DOI：
10.1021/bi052337p
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发表时间：
2006-03-14
期刊：
影响因子：
2.9
通讯作者：
Lybrand, TP
中科院分区：
文献类型：
--
作者：
Furse, KE;Pratt, DA;Lybrand, TP
环氧合酶（考克斯）酶负责前列腺素生物合成中的关键步骤，即产生前列腺素H-2。因此，这些酶是非甾体抗炎药（如阿司匹林和新的考克斯-2选择性抑制剂）的重要靶点。环氧合酶是功能性同源二聚体，并且每个亚基含有环氧合酶和过氧化物酶活性位点。这些酶是相当有趣的机械，因为花生四烯酸转化为前列腺素H-2需要两个氧化和两个环化反应，导致在形成五个新的手性中心，几乎绝对的区域和立体化学保真度。我们已经使用分子动力学（MD）模拟研究的平衡行为的考克斯-1和考克斯-2酶异构体与结合花生四烯酸。这些模拟进行了比较，与参考模拟的花生四烯酸在溶液中，以探索底物构象和定位的活性位点上的酶的效果。模拟结果表明，底物在考克斯-2活性位点具有更大的构象自由度，这与在X射线晶体结构中观察到的更大的考克斯-2活性位点体积一致。模拟揭示了不同的构象行为花生四烯酸在每个亚基在扩展的平衡MD模拟的过程中。模拟还提供了几个蛋白质通道，可能是重要的氧和水运输到或从活性位点或中间运输之间的环氧合酶和过氧化物酶活性位点的详细信息。对考克斯-1和考克斯-2活性位点结构变化的详细比较也可以为设计新的同工酶选择性抑制剂提供有用的信息。
The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H-2. As a result, these enzymes are pharmacologically important targets for nonsteroidal anti inflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H-2 requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simulations reveal different conformational behavior for arachidonate in each subunit over the course of extended equilibrium MD simulations. The simulations also provide detailed information for several protein channels that might be important for oxygen and water transport to or from active sites or for intermediate trafficking between the cyclooxygenase and peroxidase active sites. The detailed comparisons for COX-1 versus COX-2 active site structural fluctuations may also provide useful information for design of new isozyme-selective inhibitors.