Minimalist explicit solvation models for surface loops in proteins.
Minimalist explicit solvation models for surface loops in proteins.
复制标题
蛋白质表面环的极简显式溶剂化模型。
DOI：
10.1021/ct0503217
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发表时间：
2006
影响因子：
5.5
通讯作者：
Meirovitch,Hagai
中科院分区：
文献类型：
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作者：
White,RonaldP;Meirovitch,Hagai
我们已经对显式水溶解的蛋白质表面环进行了分子动力学模拟，其中研究的主要焦点是所使用的少量显式水分子(例如∼100)。这些模型只包括蛋白质的一部分(通常是500个−，1000个原子)，水分子被限制在环周围的区域。在这项研究中，水分子的数量(Nw)是系统地变化的，并与一个大的Nw会聚在一起，以揭示Nw(Min)，这是环路表现出真实(完全水合)行为所需的最小数量。我们还研究了蛋白质表面覆盖率，以及水分子的扩散和停留时间作为Nw的函数。还对其他一些建模参数进行了测试。这些包括在模型中明确考虑的环境蛋白质原子的数量，以及两种将水分子限制在环路附近的方法(我们发现其中一种方法在Nw较小时执行得更好)。将所得结果(四个回路的均方根偏差及其波动)进一步与更大的完全溶剂化体系(使用周期边界条件下的∼10 000水分子和埃瓦尔德静电学)以及广义玻恩表面积隐式溶剂化模型的结果进行了比较。我们发现，环状主干可以用令人惊讶的少量水分子(每个氨基酸残基低至5个分子)稳定下来。环路的侧链需要一个稍大的Nw，如果Nw进一步减小，原子涨落就会变得太小。因此，一般来说，我们发现在每个残基大约12个水分子时发生足够的水化。这是一个重要的结果，因为在这种水化水平上，计算时间与GBSA所需的时间相当。因此，这些“极简主义显式模型”可以提供一种可行的、可能更准确的替代方案。蛋白质环模型的重要性是在这些和其他环模型的背景下讨论的，以及其他挑战，包括适当的自由能模拟方法与构象稳定性评估的相关性。
We have performed molecular dynamics simulations of protein surface loops solvated by explicit water, where a prime focus of the study is the small numbers (e.g., ∼100) of explicit water molecules employed. The models include only part of the protein (typically 500−1000 atoms), and the water molecules are restricted to a region surrounding the loop. In this study, the number of water molecules (Nw) is systematically varied, and convergence with a largeNwis monitored to revealNw(min), the minimum number required for the loop to exhibit realistic (fully hydrated) behavior. We have also studied protein surface coverage, as well as diffusion and residence times for water molecules as a function ofNw. A number of other modeling parameters are also tested. These include the number of environmental protein atoms explicitly considered in the model as well as two ways to constrain the water molecules to the vicinity of the loop (where we find one of these methods to perform better whenNwis small). The results (for the root-mean-square deviation and its fluctuations for four loops) are further compared to much larger, fully solvated systems (using ∼10 000 water molecules under periodic boundary conditions and Ewald electrostatics) and to results for the generalized Born surface area (GBSA) implicit solvation model. We find that the loop backbone can stabilize with a surprisingly small number of water molecules (as low as five molecules per amino acid residue). The side chains of the loop require a somewhat largerNw, where the atomic fluctuations become too small ifNwis further reduced. Thus, in general, we find adequate hydration to occur at roughly 12 water molecules per residue. This is an important result because, at this hydration level, computational times are comparable to those required for GBSA. Therefore, these “minimalist explicit models” can provide a viable and potentially more accurate alternative. The importance of protein loop modeling is discussed in the context of these, and other, loop models, along with other challenges including the relevance of an appropriate free-energy simulation methodology for the assessment of conformational stability.