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首页> 外文期刊>RSC Advances >Complete sampling of an enzyme reaction pathway: a lesson from gas phase simulations
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Complete sampling of an enzyme reaction pathway: a lesson from gas phase simulations

机译：酶反应途径的完整采样：气相模拟的教训

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This work addresses the sampling issue commonly accompanying the simulation of chemical reactions. Very often the sampling is severely limited by complexity of the phase space, possibly leading to poorly converged or inaccurate free energy profiles. We explored the factors governing the completeness of reaction path sampling for the rate limiting step of phenylethylamine oxidation by lumiflavin in the gas phase, a reaction important for the pharmacology of the central nervous system. The simulations utilize the free energy perturbation sampling technique together with the empirical valence bond methodology for the free energy calculations. The simplicity of the system allows for the acquisition of fully converged free energy profiles, even for simulation free of restraints. The bottleneck for convergence is in the noticeably poorer sampling statistics in the transition state region, which is resolved by performing sufficiently long simulation to ensure reversibility of all processes accompanying the reaction. In the present case, convergence is attained in microseconds of simulation, but the required simulation time generally depends on the complexity of the potential energy surface pertinent to the reaction. Accordingly, the use of restraints reduces the complexity of the phase space, decreasing the required time by about an order of magnitude. In the case of elementary nucleophilic substitution with even simpler potential energy surface convergence is reached already at a timescale of few nanoseconds. For related biomolecular reactions embedded in an enzyme, significantly longer simulation times may be needed, rendering the sampling problem exceedingly difficult and representing a challenge for advanced sampling techniques. Accordingly, suggestions are given for optimal simulation of biomolecular reactions based on the presently employed techniques and under the aforementioned limitations.
机译：这项工作解决了通常伴随化学反应模拟的采样问题。通常，采样会受到相空间复杂性的严重限制，可能会导致收敛不佳或不准确的自由能曲线。我们探索了在气相中鲁米黄素在苯乙胺氧化的限速步骤中控制反应路径采样完成性的因素，该反应对中枢神经系统的药理学很重要。该模拟利用自由能扰动采样技术以及经验价键方法进行自由能计算。系统的简单性使得即使没有约束也可以获取完全收敛的自由能分布。收敛的瓶颈在于过渡状态区域的采样统计数据明显较差，这可以通过执行足够长的模拟来确保伴随反应的所有过程的可逆性来解决。在当前情况下，收敛以微秒的模拟实现，但是所需的模拟时间通常取决于与反应相关的势能面的复杂性。因此，约束的使用降低了相空间的复杂性，将所需时间减少了大约一个数量级。在具有甚至更简单的势能的基本亲核取代的情况下，已经在几纳秒的时间尺度上达到了表面收敛。对于嵌入酶中的相关生物分子反应，可能需要更长的模拟时间，这使采样问题变得异常困难，并代表了先进采样技术的挑战。因此，提出了基于当前采用的技术并在上述限制下对生物分子反应进行最佳模拟的建议。

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