Addressing open questions about phosphate hydrolysis pathways by careful free energy mapping.
Addressing open questions about phosphate hydrolysis pathways by careful free energy mapping.
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DOI：
10.1021/jp309778n
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发表时间：
2013-01-10
影响因子：
3.3
通讯作者：
Warshel, Arieh
中科院分区：
文献类型：
--
作者：
Prasad, B. Ram;Plotnikov, Nikolay V.;Warshel, Arieh
鉴于磷酸盐水解反应在关键生物过程中的关键作用，磷酸盐水解反应的性质和机制引起了人们的极大兴趣。虽然越来越清楚的是，解决机械争议的最终方法必须涉及可靠的理论研究，但人们并没有广泛意识到此类研究不能通过使用大多数现有的自动化方法来进行，并且只有仔细的系统绘图方法才能得出有意义的结论。目前的工作通过考虑磷酸单酯的水解来阐明上述观点。澄清首先定义应该在仔细研究中解决的实际问题，并强调忽视独特机械定义需求的研究的问题（例如，混淆联想和解离途径的研究）。然后，我们重点分析磷酸盐水解中的质子转移 (PT) 途径，以及最近提出的 PT 涉及多个水分子的建议。在这里我们指出，大多数发现质子通过多个水分子转移的研究并未涉及对相关反应坐标的系统搜索。这包括能量最小化方法以及最近的元动力学 (MTD) 模拟研究。为了说明可靠地探索潜在表面的关键需求，而不是依赖自动化方法，我们在此对沿 3D 反应坐标 (RC) 的自由能图景进行了非常仔细的研究，探索标准 2D RC（包括攻击和离去基团反应坐标）以及质子转移 (PT) 坐标。我们的研究指出，QM/MM 最小化或 MTD 研究得出的结论是磷酸单酯的水解涉及通过多个水分子的 PT，但尚未探索单一水 (1W) 路径（涉及从攻击水分子到磷酸氧的直接 PT）。此外，我们还确定了通过 QM/MM 最小化方法以及当前的 MTD 模拟难以找到 1W 路径的最可能原因。我们还讨论了当前研究挑战磷酸盐作为基本机制的问题。也许最重要的是，我们澄清并说明了替代途径的关键机械问题不应通过运行黑盒搜索方法来探索。
The nature and mechanism of phosphate hydrolysis reactions are of great interest in view of the crucial role of these reactions in key biological processes. While it is becoming clearer that the ultimate way of resolving mechanistic controversies must involve reliable theoretical studies, it is not widely realized that such studies cannot be performed by using most existing automated ways and that only careful systematic mapping approach can lead to meaningful conclusions. The present work clarifies the above point by considering the hydrolysis of phosphate monoesters. The clarification starts by defining the actual issues that should be addressed in careful studies, and by highlighting the problems with studies that ignore the need for unique mechanistic definitions (e.g., works that confuse associative and dissociative pathways). We then focus on the analysis of the proton transfer (PT) pathways in phosphate hydrolysis and on recent suggestions that PT involves more than one water molecule. Here we point out that most of the studies that found a proton transfer through several water molecules have not involved a systematic search of the relevant reaction coordinates. This includes both energy minimization approaches as well as a recent metadynamics (MTD) simulation study. To illustrate the crucial need of exploring the potential surfaces reliably, rather than relying on automated approaches, we present here a very careful study of the free energy landscape along a 3D reaction coordinate (RC) exploring both the standard 2D RC, comprised of the attacking and leaving group reaction coordinates, as well as of the proton transfer (PT) coordinate. Our study points out that that QM/MM minimization or MTD studies, that concluded that the hydrolysis of phosphate monoesters involves a PT through several water molecules, have not explored the single water (1W) path (that involves a direct PT form the attacking water molecule to the phosphate oxygen). Furthermore, we identified the most likely reason for the difficulty in finding the 1W path by QM/MM minimization methods, as well as by the current MTD simulations. We also discuss the problems with current studies that challenge the phosphate as a base mechanism. Perhaps most importantly, we clarify and illustrate that crucial mechanistic problems with alternative pathways should not be explored by running black box search approaches.
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影响因子：
6.1
作者：
Kamerlin SC;Sharma PK;Prasad RB;Warshel A
通讯作者：
Warshel A
影响因子：
15
作者：
Guthrie, JP
通讯作者：
Guthrie, JP
DOI：
10.1073/pnas.0608952104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Castro, Christian;Smidansky, Eric;Cameron, Craig E.
通讯作者：
Cameron, Craig E.
影响因子：
5.5
作者：
Harrison, Christopher B.;Schulten, Klaus
通讯作者：
Schulten, Klaus
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD