Continuous Constant pH Molecular Dynamics in Explicit Solvent with pH-Based Replica Exchange.
Continuous Constant pH Molecular Dynamics in Explicit Solvent with pH-Based Replica Exchange.
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DOI：
10.1021/ct200146j
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发表时间：
2011-08-09
影响因子：
5.5
通讯作者：
Shen JK
中科院分区：
文献类型：
--
作者：
Wallace JA;Shen JK
一个计算工具，提供准确的pKa值和质子耦合构象动力学的原子详细的知识是有价值的阐明生物学中的能量转导过程，如酶催化，电子转移，以及质子和药物的运输机制。为了实现这一目标，我们提出了一种新的技术，嵌入连续恒定pH分子动力学内的显式溶剂表示。在这项技术中，我们利用广义玻恩（GB）隐式溶剂模型的效率估计蛋白质溶剂化的自由能，同时使用更准确的显式溶剂模型传播构象动力学。此外，我们采用了基于pH值的副本交换计划，显着提高质子化和构象状态采样。包括HP36、NTL9、BBL、HEWL和SNase在内的五种蛋白质的基准数据与实验数据的平均绝对偏差为0.53，均方根偏差为0.74。这种精度水平是通过每个副本的1 ns模拟获得的。详细的分析表明，显式溶剂采样提供了更高的准确性相对于以前的GB为基础的方法，通过保留天然结构，提供了一个更现实的描述的疏水簇的构象灵活性，并正确建模溶剂介导的离子对相互作用。因此，我们预计，新技术将成为一个实用的工具，以捕捉电离平衡，同时使一个亲密的看法电离耦合构象动力学，这是很难单独描绘与实验技术。
A computational tool that offers accurate pKa values and atomically detailed knowledge of protonation-coupled conformational dynamics is valuable for elucidating mechanisms of energy transduction processes in biology such as enzyme catalysis, electron transfer, as well as proton and drug transport. Towards this goal we present a new technique of embedding continuous constant pH molecular dynamics within an explicit-solvent representation. In this technique we make use of the efficiency of the Generalized-Born (GB) implicit-solvent model for estimating the free energy of protein solvation, while propagating conformational dynamics using the more accurate explicit-solvent model. Also, we employ a pH-based replica exchange scheme to significantly enhance both protonation and conformational state sampling. Benchmark data of five proteins including HP36, NTL9, BBL, HEWL, and SNase yield an average absolute deviation of 0.53 and a root mean squared deviation of 0.74 from experimental data. This level of accuracy is obtained with 1-ns simulations per replica. Detailed analysis reveals that explicit-solvent sampling provides increased accuracy relative to the previous GB-based method by preserving the native structure, providing a more realistic description of conformational flexibility of the hydrophobic cluster, and correctly modeling solvent mediated ion-pair interactions. Thus, we anticipate that the new technique will emerge as a practical tool to capture ionization equilibria while enabling an intimate view of ionization-coupled conformational dynamics that is difficult to delineate with experimental techniques alone.
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