Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles
Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles
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DOI：
10.1021/acs.jcim.1c00161
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发表时间：
2021-05-24
影响因子：
5.6
通讯作者：
Pogozheva, Irina D.
中科院分区：
文献类型：
--
作者：
Lomize, Andrei L.;Schnitzer, Kevin A.;Pogozheva, Irina D.
建立了折叠膜相关肽（FMAP）方法，用于模拟胶束和脂质双层中线性肽的α -螺旋形成。FMAP 2.0识别氨基酸序列中α -螺旋的位置，在平面双层或球形胶束中生成它们的三维模型，并根据温度和ph值估计它们的热力学稳定性和倾斜角度。该方法在不同环境下实验研究了723个肽（926个数据点）和170个具有可用晶体结构的单遍跨膜（TM）蛋白质中进行了测试。FMAP 2.0可以检测到95%以上的实验观察到的α -螺旋，对于水、胶束、双层和TM蛋白中的肽，在螺旋末端的平均误差分别为每个螺旋约2、3、4和5个残基。螺旋态和非螺旋态的预测精度在0.86 ~ 0.96之间，马修斯相关系数在0.64 ~ 0.88之间。实验结果显示，多肽的胶束结合能和膜结合能以及倾斜角度的均方根偏差分别约为2 kcal/mol和7度。在95%以上的病例中，各种脂质双层中疏水和ph触发的α -螺旋肽的TM和非TM状态得以再现。FMAP 2.0 web服务器（https://membranome.org/fmap）可用于探索抗菌肽、细胞穿透肽、融合肽和其他膜结合肽的结构多态性，这对了解其生物活性机制非常重要。
The Folding of Membrane-Associated Peptides (FMAP) method was developed for modeling alpha-helix formation by linear peptides in micelles and lipid bilayers. FMAP 2.0 identifies locations of alpha-helices in the amino acid sequence, generates their three-dimensional models in planar bilayers or spherical micelles, and estimates their thermodynamic stabilities and tilt angles, depending on temperature and pH. The method was tested for 723 peptides (926 data points) experimentally studied in different environments and for 170 single-pass transmembrane (TM) proteins with available crystal structures. FMAP 2.0 detected more than 95% of experimentally observed alpha-helices with an average error in helix end determination of around 2, 3, 4, and 5 residues per helix for peptides in water, micelles, bilayers, and TM proteins, respectively. Helical and nonhelical residue states were predicted with an accuracy from 0.86 to 0.96, and the Matthews correlation coefficient was from 0.64 to 0.88 depending on the environment. Experimental micelle- and membrane-binding energies and tilt angles of peptides were reproduced with a root-mean-square deviation of around 2 kcal/mol and 7 degrees, respectively. The TM and non-TM states of hydrophobic and pH-triggered alpha-helical peptides in various lipid bilayers were reproduced in more than 95% of cases. The FMAP 2.0 web server (https://membranome.org/fmap) is publicly available to explore the structural polymorphism of antimicrobial, cell-penetrating, fusion, and other membrane-binding peptides, which is important for understanding the mechanisms of their biological activities.