Making optimal use of empirical energy functions: Force-field parameterization in crystal space
Making optimal use of empirical energy functions: Force-field parameterization in crystal space
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DOI：
10.1002/prot.20251
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发表时间：
2004-12-01
影响因子：
2.9
通讯作者：
Vriend, G
中科院分区：
文献类型：
--
作者：
Krieger, E;Darden, T;Vriend, G
今天的能量函数还不能可靠地区分正确和几乎正确的蛋白质模型。改进这些近原生模型是目前同源建模或低分辨率实验结构确定的主要瓶颈。例如，在分子动力学模拟过程中，需要越来越精确的能量函数来完成“蛋白质折叠问题的最后一英里”。我们提出了一种实现这一目标的新方法。对于50个高分辨率x射线结构，重建了完整的单位细胞，包括无序的水分子，反离子和氢原子。然后在解决晶体的pH值下进行模拟，同时迭代调整力场参数，以使对结构的破坏最小。从AMBER力场的初始参数开始，优化过程收敛到一个名为YAMBER （Yet Another Model Building and Energy Refinement force field）的新力场，该力场对x射线结构的损伤明显更小，通常会使同源模型朝着正确的方向移动，偶尔会使它们看起来像实验结构。将YAMBER应用于CASP5结构预测实验，得到目标176的模型，在150个提交的模型中排名第一。由于其与完善的琥珀格式的兼容性，YAMBER可以被几乎任何分子动力学程序使用。这些参数可以从www.yasara.org/ yamber免费获得。(C) 2004 Wiley-Liss, Inc。
Today's energy functions are not able yet to distinguish reliably between correct and almost correct protein models. Improving these near-native models is currently a major bottle-neck in homology modeling or experimental structure determination at low resolution. Increasingly accurate energy functions are required to complete the "last mile of the protein folding problem," for example during a molecular dynamics simulation. We present a new approach to reach this goal. For 50 high resolution X-ray structures, the complete unit cell was reconstructed, including disordered water molecules, counter ions, and hydrogen atoms. Simulations were then run at the pH at which the crystal was solved, while force-field parameters were iteratively adjusted so that the damage done to the structures was minimal. Starting with initial parameters from the AMBER force field, the optimization procedure converged at a new force field called YAMBER (Yet Another Model Building and Energy Refinement force field), which is shown to do significantly less damage to X-ray structures, often move homology models in the right direction, and occasionally make them look like experimental structures. Application of YAMBER during the CASP5 structure prediction experiment yielded a model for target 176 that was ranked first among 150 submissions. Due to its compatibility with the well-established AMBER format, YAMBER can be used by almost any molecular dynamics program. The parameters are freely available from www.yasara.org/ yamber. (C) 2004 Wiley-Liss, Inc.