Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
J Phys Chem B. 2011 May 19;115(19):5958-70. doi: 10.1021/jp1076802. Epub 2011 Apr 19.
The covalent stability of peptide bonds is a critical aspect of biological chemistry and therapeutic protein applications. In this computational study, the hydrolytic reaction of peptide bonds at neutral pH was studied using a model compound, N-MAA. The most probable reaction pathway and intermediate(s) involved are controversial in previous studies. In addition, most previous computational studies focus on the energetics of chemical species involved, rather than providing a dynamic picture of the reaction process in aqueous conditions. However, fluctuations at finite temperatures are quite important, as we show. Thus, a path sampling method was used to generate an ensemble of trajectories according to their statistical weights in trajectory space. An ab initio molecular dynamics technique was applied to advance the time of the reaction in order to collect trajectories. The likelihood maximization procedure and its modification were used in extracting dynamically relevant degrees of freedom in the system, and approximations of the reaction coordinate were compared. It was found that this hydrolytic reaction is very complex because it involves many degrees of freedom. The reaction coordinate C-O distance previously assumed was found to be inadequate in describing the dynamic progress of the reaction. In addition to affecting atoms directly involved in bond-making and -breaking processes, the water network also has determining effects on the hydrolytic reaction, a fact which is manifest in the expression of the best one-dimensional reaction coordinate that we found, which includes five geometric quantities. p(B) histograms were computed to verify the results of the likelihood maximization and to evaluate the accuracy of our best reaction coordinate to the "true" reaction coordinate. The relation with previous suggested reaction pathways and intermediate(s) is discussed in terms of computational system, method, and accuracy.
肽键的共价稳定性是生物化学和治疗性蛋白质应用的一个关键方面。在这项计算研究中，使用模型化合物 N-MAA 研究了中性 pH 下肽键的水解反应。在以前的研究中，最可能的反应途径和中间体存在争议。此外，大多数以前的计算研究侧重于涉及的化学物质的能量学，而不是提供在水相条件下反应过程的动态图像。然而，我们表明，在有限温度下的波动非常重要。因此，使用路径采样方法根据轨迹空间中的统计权重生成轨迹的集合。应用从头算分子动力学技术推进反应时间以收集轨迹。似然最大化程序及其修改用于提取系统中动态相关的自由度，并比较了反应坐标的近似值。结果发现，由于涉及许多自由度，因此这种水解反应非常复杂。以前假设的反应坐标 C-O 距离在描述反应的动态进展时不够充分。除了直接影响参与成键和断键过程的原子外，水网络对水解反应也有决定性的影响，这一事实在我们发现的最佳一维反应坐标的表达式中表现出来，其中包括五个几何量。计算了 p(B) 直方图以验证似然最大化的结果，并评估我们最佳反应坐标对“真实”反应坐标的准确性。根据计算系统、方法和准确性讨论了与以前建议的反应途径和中间体的关系。
