Department of Biochemistry & Molecular Biology and Centre for Genomics and Evolutionary Bioinformatics, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
J Chem Inf Model. 2010 Dec 27;50(12):2213-20. doi: 10.1021/ci100324n. Epub 2010 Nov 19.
Although the α-helical secondary structure of proteins is well-defined, the exact causes and structures of helical kinks are not. This is especially important for transmembrane (TM) helices of integral membrane proteins, many of which contain kinks providing functional diversity despite predominantly helical structure. We have developed a Monte Carlo method based algorithm, MC-HELAN, to determine helical axes alongside positions and angles of helical kinks. Analysis of all nonredundant high-resolution α-helical membrane protein structures (842 TM helices from 205 polypeptide chains) revealed kinks in 64% of TM helices, demonstrating that a significantly greater proportion of TM helices are kinked than those indicated by previous analyses. The residue proline is over-represented by a factor >5 if it is two or three residues C-terminal to a bend. Prolines also cause kinks with larger kink angles than other residues. However, only 33% of TM kinks are in proximity to a proline. Machine learning techniques were used to test for sequence-based predictors of kinks. Although kinks are somewhat predicted by sequence, kink formation appears to be driven predominantly by other factors. This study provides an improved view of the prevalence and architecture of kinks in helical membrane proteins and highlights the fundamental inaccuracy of the typical topological depiction of helical membrane proteins as series of ideal helices.
尽管蛋白质的α-螺旋二级结构是明确的，但螺旋扭曲的确切原因和结构尚不清楚。这对于整合膜蛋白的跨膜（TM）螺旋尤其重要，其中许多螺旋包含扭曲，尽管主要呈螺旋结构，但提供了功能多样性。我们开发了一种基于蒙特卡罗方法的算法 MC-HELAN，用于确定螺旋轴以及螺旋扭曲的位置和角度。对所有非冗余的高分辨率α-螺旋膜蛋白结构（来自 205 条多肽链的 842 个 TM 螺旋）进行分析，结果显示 64%的 TM 螺旋存在扭曲，这表明与之前的分析相比，更多的 TM 螺旋发生了扭曲。如果脯氨酸位于弯曲的两个或三个残基 C 末端，则其出现的频率会超过其他残基的 5 倍。脯氨酸也会导致扭曲角大于其他残基的扭曲。然而，只有 33%的 TM 扭曲与脯氨酸接近。机器学习技术被用于测试基于序列的扭曲预测因子。尽管扭曲在一定程度上可以通过序列预测，但扭曲的形成似乎主要是由其他因素驱动的。这项研究提供了对螺旋膜蛋白中扭曲的普遍性和结构的更深入了解，并强调了典型的螺旋膜蛋白拓扑描述作为一系列理想螺旋的基本不准确性。
