Jagielska Anna, Wroblewska Liliana, Skolnick Jeffrey
Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 250 14th Street NW, Atlanta, GA 30318, USA.
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8268-73. doi: 10.1073/pnas.0800054105. Epub 2008 Jun 11.
One of the greatest challenges in protein structure prediction is the refinement of low-resolution predicted models to high-resolution structures that are close to the native state. Although contemporary structure prediction methods can assemble the correct topology for a large fraction of protein domains, such approximate models are often not of the resolution required for many important applications, including studies of reaction mechanisms and virtual ligand screening. Thus, the development of a method that could bring those structures closer to the native state is of great importance. We recently optimized the relative weights of the components of the Amber ff03 potential on a large set of decoy structures to create a funnel-shaped energy landscape with the native structure at the global minimum. Such an energy function might be able to drive proteins toward their native structure. In this work, for a test set of 47 proteins, with 100 decoy structures per protein that have a range of structural similarities to the native state, we demonstrate that our optimized potential can drive protein models closer to their native structure. Comparing the lowest-energy structure from each trajectory with the starting decoy, structural improvement is seen for 70% of the models on average. The ability to do such systematic structural refinements by using a physics-based all-atom potential represents a promising approach to high-resolution structure prediction.
蛋白质结构预测中最大的挑战之一是将低分辨率的预测模型精修至接近天然状态的高分辨率结构。尽管当代结构预测方法能够为大部分蛋白质结构域组装正确的拓扑结构，但这种近似模型往往达不到许多重要应用（包括反应机制研究和虚拟配体筛选）所需的分辨率。因此，开发一种能使这些结构更接近天然状态的方法至关重要。我们最近在一大组诱饵结构上优化了Amber ff03势的各组分的相对权重，以创建一个漏斗形的能量景观，其中天然结构处于全局最小值。这样的能量函数或许能够驱使蛋白质趋向其天然结构。在这项工作中，对于一个包含47种蛋白质的测试集，每种蛋白质有100个与天然状态具有一系列结构相似性的诱饵结构，我们证明了我们优化后的势能够驱使蛋白质模型更接近其天然结构。将每个轨迹中的最低能量结构与起始诱饵进行比较，平均70%的模型在结构上有改进。利用基于物理的全原子势进行这种系统的结构精修的能力代表了一种有前景的高分辨率结构预测方法。
