Highly Efficient Computation of the Basal kon using Direct Simulation of Protein-Protein Association with Flexible Molecular Models.
Highly Efficient Computation of the Basal kon using Direct Simulation of Protein-Protein Association with Flexible Molecular Models.
复制标题
使用蛋白质 - 蛋白质与柔性分子模型的蛋白质蛋白关联直接模拟基础KON的高效计算。
DOI：
10.1021/acs.jpcb.5b10747
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发表时间：
2016-01-14
期刊：
影响因子：
--
通讯作者：
Chong LT
中科院分区：
文献类型：
--
作者：
Saglam AS;Chong LT
用于确定静电相互作用增强蛋白质-蛋白质缔合动力学的程度的基本基线是“基础”kon，其是在不存在静电相互作用的情况下缔合的速率常数。然而，由于这种关联事件超出毫秒时间尺度，因此通过直接模拟与灵活模型的关联来计算基础kon是不切实际的。在这里，我们使用高效、灵活的分子模拟计算了芽孢杆菌RNA酶和芽孢杆菌RNA酶抑制剂的基础kon，这两种蛋白质是最快速结合的蛋白质。这些模拟涉及（a）伪原子蛋白质模型，再现了全原子模型的分子形状，静电和扩散特性，以及（B）加权系综路径采样策略的应用，该策略将产生关联事件的效率提高了130倍以上。我们还研究了在何种程度上计算的基础kon的影响，包括分子间的流体动力学相互作用的模拟。
An essential baseline for determining the extent to which electrostatic interactions enhance the kinetics of protein–protein association is the “basal” kon, which is the rate constant for association in the absence of electrostatic interactions. However, since such association events are beyond the milliseconds time scale, it has not been practical to compute the basal kon by directly simulating the association with flexible models. Here, we computed the basal kon for barnase and barstar, two of the most rapidly associating proteins, using highly efficient, flexible molecular simulations. These simulations involved (a) pseudoatomic protein models that reproduce the molecular shapes, electrostatic, and diffusion properties of all-atom models, and (b) application of the weighted ensemble path sampling strategy, which enhanced the efficiency of generating association events by >130-fold. We also examined the extent to which the computed basal kon is affected by inclusion of intermolecular hydrodynamic interactions in the simulations.