Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests
Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests
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DOI：
10.1073/pnas.0502655102
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发表时间：
2005-05-24
影响因子：
11.1
通讯作者：
Scheraga, HA
中科院分区：
文献类型：
--
作者：
Oldziej, S;Czaplewski, C;Scheraga, HA
最近的改进，在我们的实验室开发的蛋白质结构预测方法，热力学假设的基础上，进行了描述。利用我们基于物理的UNRES能量函数和全局优化的构象空间退火方法，在联合残基水平上广泛搜索构象空间。最低能量的粗粒度结构，然后转换为一个全原子表示和能量最小化的ECEPP/3力场。该程序在最近的两个蛋白质结构预测盲测中进行了评估。在第一次盲测期间，我们预测了α和α + β蛋白的大片段[60-70个残基，C-alpha rms偏差（rmsd）< 6 A]。然而，对于α + β蛋白，尽管rmsd值较低，但仍发生了显著的拓扑错误。在第二个练习中，我们预测了五种蛋白质（两种α和三种α + β，大小为53-235个残基）的整个结构，具有非常好的准确性。特别是，对于基因组靶标TM 0487（来自海栖热袍菌的102个残基的α + β蛋白），我们预测了具有7.3埃C-α rmsd的完整的拓扑正确结构。到目前为止，该蛋白是仅基于氨基酸序列和基于物理学的势能函数和搜索程序预测的最大的α + β蛋白。对于靶标T0198，来自T. maritima（235个残基，主要是α-螺旋蛋白），除了32个C-末端残基，大部分形成β-发夹结构，我们在8A rmsd内正确预测了整个六螺旋束的拓扑结构。本工作中描述的这些和其他例子证明了基于物理的蛋白质结构预测的重大进展。
Recent improvements in the protein-structure prediction method developed in our laboratory, based on the thermodynamic hypothesis, are described. The conformational space is searched extensively at the united-residue level by using our physics-based UNRES energy function and the conformational space annealing method of global optimization. The lowest-energy coarse-grained structures are then converted to an all-atom representation and energy-minimized with the ECEPP/3 force field. The procedure was assessed in two recent blind tests of protein-structure prediction. During the first blind test, we predicted large fragments of a and alpha+beta proteins [60-70 residues with C-alpha rms deviation (rmsd) < 6 A]. However, for alpha+beta proteins, significant topological errors occurred despite low rmsd values. In the second exercise, we predicted whole structures of five proteins (two a and three alpha+beta, with sizes of 53-235 residues) with remarkably good accuracy. In particular, for the genomic target TM0487 (a 102-residue alpha+beta protein from Thermotoga maritima), we predicted the complete, topologically correct structure with 7.3-angstrom C-alpha rmsd. So far this protein is the largest alpha+beta protein predicted based solely on the amino acid sequence and a physics-based potential-energy function and search procedure. For target T0198, a phosphate transport system regulator PhoU from T. maritima (a 235-residue mainly a-helical protein), we predicted the topology of the whole six-helix bundle correctly within 8 A rmsd, except the 32 C-terminal residues, most of which form a beta-hairpin. These and other examples described in this work demonstrate significant progress in physics-based protein-structure prediction.