Improving Protocols for Protein Mapping through Proper Comparison to Crystallography Data
Improving Protocols for Protein Mapping through Proper Comparison to Crystallography Data
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DOI：
10.1021/ci300430v
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发表时间：
2013-02-01
影响因子：
5.6
通讯作者：
Carlson, Heather A.
中科院分区：
文献类型：
--
作者：
Lexa, Katrina W.;Carlson, Heather A.
基于片段的药物设计（FBDD）的计算方法可以补充实验并促进沿蛋白质表面潜在热点的识别。然而，对结合位点定位计算方法的评价往往集中在再现晶体坐标到低RMSD阈值的能力上。这种对沉积坐标数据的依赖忽略了实验中原始的电子密度，因此技术可能是基于主观的甚至是错误的原子坐标来开发的。在热点位置未知的系统应用程序中，这可能成为一个重大缺陷。在与晶体密度比较的基础上，我们之前发现混合溶剂分子动力学（MixMD）以乙腈为有机溶剂准确地识别了HEWL的活性位点。在这里，我们集中研究了质子溶剂对模拟的影响，并改进了MixMD方法的最佳方法，以便将该方法外推到没有确定位点的系统。我们的结果建立了一个精确的方法来比较模拟和实验。我们已经根据模拟长度和运行次数概述了MixMD最有效的策略。这里概述的开发使MixMD成为一种健壮的方法，它应该在广泛的目标结构中证明是有用的。最后，我们的MixMD结果与实验数据吻合得很好，模拟和密度之间的一致性可能是在未来多溶剂晶体结构改进过程中帮助识别探针与水的有用方法。
Computational approaches to fragment-based drug design (FBDD) can complement experiments and facilitate the, identification of potential hot spots along the protein surface. However, the evaluation of computational methods for mapping binding sites frequently focuses upon the ability to reproduce crystallographic coordinates to within a low RMSD threshold. This dependency on the deposited coordinate data overlooks the original electron density from the experiment, thus techniques may be developed based upon subjective-or even erroneous-atomic coordinates. This can become a significant drawback in applications to systems where the location of hot spots is unknown. On the basis of comparison to crystallographic density, we previously showed that mixed-solvent molecular dynamics (MixMD) accurately identifies the active site for HEWL, with acetonitrile as an organic solvent. Here, we concentrated on the influence of protic solvent on simulation and refined the optimal MixMD approach for extrapolation of the method to systems without established sites. Our results establish an accurate approach for comparing simulations to experiment. We have outlined the most efficient strategy for MixMD, based on simulation length and number of runs. The development outlined here makes MixMD a robust method which should prove useful across a broad range of target structures. Lastly, our results with MixMD match experimental data so well that consistency between simulations and density may be a useful way to aid the identification of probes vs waters during the refinement of future multiple solvent crystallographic structures.