Position-resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations
Position-resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations
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DOI：
10.1002/prot.21629
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发表时间：
2008-03-01
影响因子：
2.9
通讯作者：
Lindahl, Erik
中科院分区：
文献类型：
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作者：
Johansson, Anna C. V.;Lindahl, Erik
氨基酸在脂膜中的插入和相互作用的研究对于我们理解膜蛋白的结构和功能是至关重要的。因此，计算插入成本作为跨膜螺旋序列的函数是改进膜蛋白预测和最终药物设计的重要一步。在这里，我们给出了沿膜法线方向的所有氨基酸类似物的位置相关的溶剂化自由能。这些轮廓覆盖了从散装水到疏水核心的整个区域，并由全原子分子动力学模拟产生。与整个链段的突变和成本相对应的实验差异与实验数据吻合得很好，此外，轮廓还提供了目前实验无法获得的空间分辨率，极性侧链基本上保持了水化作用，并呈现出非常有序的构象，这表明溶剂化成本主要是熵的。带电侧链的溶剂化成本不仅显著低于隐式溶剂化模型，而且接近实验，这意味着这些模型可以很好地保持膜内的质子化状态。实验协议中唯一值得注意的例外是脯氨酸，尽管它具有疏水性，但在体内引入它是相当昂贵的-这种差异可能是由于扭结使在转位基因中插入螺旋变得更加困难。
Studies of insertion and interactions Of amino acids in lipid membranes are pivotal to our understanding of membrane protein structure and function. Calculating the insertion cost as a function of transmembrane helix sequence is thus an important step towards improved membrane protein prediction and eventually drug design. Here, we present position-dependent free energies of solvation for all amino acid analogs along the membrane normal. The profiles cover the entire region from bulk water to hydrophobic core, and were produced from all-atom molecular dynamics simulations. Experimental differences corresponding to mutations and costs for entire segments match experimental data well, and in addition the profiles provide the spatial resolution currently not available from experiments.Polar side-chains largely maintain their hydration and assume quite ordered conformations, which indicates the solvation cost is mainly entropic. The cost of solvating charged side-chains is not only significantly lower than for implicit solvation models, but also close to experiments, meaning these could well maintain their protonation states inside the membrane. The single notable exception to the experimental agreement is proline, which is quite expensive to introduce in vivo despite its hydrophobicity-a difference possibly explained by kinks making it harder to insert helices in the translocon.