Park Yungki, Helms Volkhard
Center for Bioinformatics, Saarland University, Saarbruecken, Germany.
Proteins. 2006 Sep 1;64(4):895-905. doi: 10.1002/prot.21025.
The transmembrane (TM) domains of most membrane proteins consist of helix bundles. The seemingly simple task of TM helix bundle assembly has turned out to be extremely difficult. This is true even for simple TM helix bundle proteins, i.e., those that have the simple form of compact TM helix bundles. Herein, we present a computational method that is capable of generating native-like structural models for simple TM helix bundle proteins having modest numbers of TM helices based on sequence conservation patterns. Thus, the only requirement for our method is the presence of more than 30 homologous sequences for an accurate extraction of sequence conservation patterns. The prediction method first computes a number of representative well-packed conformations for each pair of contacting TM helices, and then a library of tertiary folds is generated by overlaying overlapping TM helices of the representative conformations. This library is scored using sequence conservation patterns, and a subsequent clustering analysis yields five final models. Assuming that neighboring TM helices in the sequence contact each other (but not that TM helices A and G contact each other), the method produced structural models of Calpha atom root-mean-square deviation (CA RMSD) of 3-5 A from corresponding crystal structures for bacteriorhodopsin, halorhodopsin, sensory rhodopsin II, and rhodopsin. In blind predictions, this type of contact knowledge is not available. Mimicking this, predictions were made for the rotor of the V-type Na(+)-adenosine triphosphatase without such knowledge. The CA RMSD between the best model and its crystal structure is only 3.4 A, and its contact accuracy reaches 55%. Furthermore, the model correctly identifies the binding pocket for sodium ion. These results demonstrate that the method can be readily applied to ab initio structure prediction of simple TM helix bundle proteins having modest numbers of TM helices.
大多数膜蛋白的跨膜（TM）结构域由螺旋束组成。TM螺旋束组装这一看似简单的任务实际上极其困难。即使对于简单的TM螺旋束蛋白，即那些具有紧凑TM螺旋束简单形式的蛋白，也是如此。在此，我们提出一种计算方法，该方法能够基于序列保守模式为具有适量TM螺旋的简单TM螺旋束蛋白生成类似天然的结构模型。因此，我们的方法唯一的要求是存在30多个同源序列，以便准确提取序列保守模式。该预测方法首先为每对相互接触的TM螺旋计算一些具有代表性的紧密堆积构象，然后通过叠加代表性构象中重叠的TM螺旋生成三级折叠文库。使用序列保守模式对该文库进行评分，随后的聚类分析产生五个最终模型。假设序列中相邻的TM螺旋相互接触（但不是TM螺旋A和G相互接触），该方法生成的细菌视紫红质、嗜盐视紫红质、感官视紫红质II和视紫红质的Cα原子均方根偏差（CA RMSD）与相应晶体结构相差3 - 5 Å的结构模型。在盲预测中，这种接触知识是不可用的。模拟这种情况，在没有这种知识的情况下对V型Na⁺ - 腺苷三磷酸酶的转子进行了预测。最佳模型与其晶体结构之间的CA RMSD仅为3.4 Å，其接触准确率达到55%。此外，该模型正确识别了钠离子的结合口袋。这些结果表明，该方法可以很容易地应用于具有适量TM螺旋的简单TM螺旋束蛋白的从头结构预测。
