Möglich Andreas, Weinfurtner Daniel, Maurer Till, Gronwald Wolfram, Kalbitzer Hans Robert
Institut für Biophysik und physikalische Biochemie, Universität Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany.
BMC Bioinformatics. 2005 Apr 8;6:91. doi: 10.1186/1471-2105-6-91.
We have developed the program PERMOL for semi-automated homology modeling of proteins. It is based on restrained molecular dynamics using a simulated annealing protocol in torsion angle space. As main restraints defining the optimal local geometry of the structure weighted mean dihedral angles and their standard deviations are used which are calculated with an algorithm described earlier by Doker et al. (1999, BBRC, 257, 348-350). The overall long-range contacts are established via a small number of distance restraints between atoms involved in hydrogen bonds and backbone atoms of conserved residues. Employing the restraints generated by PERMOL three-dimensional structures are obtained using standard molecular dynamics programs such as DYANA or CNS.
To test this modeling approach it has been used for predicting the structure of the histidine-containing phosphocarrier protein HPr from E. coli and the structure of the human peroxisome proliferator activated receptor gamma (Ppar gamma). The divergence between the modeled HPr and the previously determined X-ray structure was comparable to the divergence between the X-ray structure and the published NMR structure. The modeled structure of Ppar gamma was also very close to the previously solved X-ray structure with an RMSD of 0.262 nm for the backbone atoms.
In summary, we present a new method for homology modeling capable of producing high-quality structure models. An advantage of the method is that it can be used in combination with incomplete NMR data to obtain reasonable structure models in accordance with the experimental data.
我们开发了用于蛋白质半自动同源建模的程序PERMOL。它基于扭转角空间中使用模拟退火协议的受限分子动力学。作为定义结构最佳局部几何形状的主要约束，使用加权平均二面角及其标准偏差，这些是通过Doker等人（1999年，《生物化学与生物物理研究通讯》，257，348 - 350）先前描述的算法计算得出的。通过参与氢键的原子与保守残基的主链原子之间的少量距离约束来建立整体远程接触。利用PERMOL生成的约束，使用诸如DYANA或CNS等标准分子动力学程序获得三维结构。
为了测试这种建模方法，已将其用于预测大肠杆菌中含组氨酸的磷酸载体蛋白HPr的结构以及人过氧化物酶体增殖物激活受体γ（Pparγ）的结构。建模的HPr与先前确定的X射线结构之间的差异与X射线结构和已发表的NMR结构之间的差异相当。Pparγ的建模结构也非常接近先前解析的X射线结构，主链原子的均方根偏差（RMSD）为0.262纳米。
总之，我们提出了一种能够生成高质量结构模型的同源建模新方法。该方法的一个优点是它可以与不完整的NMR数据结合使用，以根据实验数据获得合理的结构模型。
