Reservoir pH replica exchange
Reservoir pH replica exchange
复制标题
水库 pH 复制交换
DOI：
10.1063/1.5027413
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发表时间：
2018-08-21
影响因子：
4.4
通讯作者：
Brooks, Bernard R.
中科院分区：
文献类型：
--
作者：
Damjanovic, Ana;Miller, Benjamin T.;Brooks, Bernard R.
我们提出了水库pH副本交换（R-pH-REM）方法的恒定pH值模拟。R-pH-REM方法由两步程序组成;第一步涉及生成一个或多个构象库。每个水库是从一个标准的或增强的分子动力学模拟与约束（固定）质子化状态。在第二步中，放松固定电荷约束，因为来自一个或多个储层的结构被周期性地注入恒定pH或pH-复制交换（pH-REM）模拟中。这个两步过程的好处是，构象搜索的计算密集型部分可以从恒定pH模拟中解耦，并且可以应用用于增强构象采样的各种技术，而不需要将这些技术集成到pH-REM框架中。封闭的赖氨酸，KK，和KAAE肽的模拟被用来证明之间的协议pHREM和R-pH-REM模拟。虽然对于这些小的测试系统不需要储层模拟，但是在可电离分子可以对由大的能量势垒分离的两种或更多种构象进行采样的情况下出现了真实的需要，使得在标准恒定pH模拟的时间尺度上不能实现足够的采样。这些问题可能会遇到蛋白质系统，利用构象转换的功能。一个假设的情况下进行了研究，一个小分子与一个大的扭转势垒，而pH-REM模拟的结果取决于起始结构，R-pH-REM计算这个模型系统是在良好的协议与理论模型。
We present the reservoir pH replica exchange (R-pH-REM) method for constant pH simulations. The R-pH-REM method consists of a two-step procedure; the first step involves generation of one or more reservoirs of conformations. Each reservoir is obtained from a standard or enhanced molecular dynamics simulation with a constrained (fixed) protonation state. In the second step, fixed charge constraints are relaxed, as the structures from one or more reservoirs are periodically injected into a constant pH or a pH-replica exchange (pH-REM) simulation. The benefit of this two-step process is that the computationally intensive part of conformational search can be decoupled from constant pH simulations, and various techniques for enhanced conformational sampling can be applied without the need to integrate such techniques into the pH-REM framework. Simulations on blocked Lys, KK, and KAAE peptides were used to demonstrate an agreement between pHREM and R-pH-REM simulations. While the reservoir simulations are not needed for these small test systems, the real need arises in cases when ionizable molecules can sample two or more conformations separated by a large energy barrier, such that adequate sampling is not achieved on a time scale of standard constant pH simulations. Such problems might be encountered in protein systems that exploit conformational transitions for function. A hypothetical case is studied, a small molecule with a large torsional barrier; while results of pH-REM simulations depend on the starting structure, R-pH-REM calculations on this model system are in excellent agreement with a theoretical model.