Partitioning of amino acid side chains into lipid bilayers: results from computer simulations and comparison to experiment.
Partitioning of amino acid side chains into lipid bilayers: results from computer simulations and comparison to experiment.
复制标题
DOI：
10.1085/jgp.200709745
复制
发表时间：
2007-05
期刊：
影响因子：
--
通讯作者：
Tieleman DP
中科院分区：
文献类型：
--
作者：
MacCallum JL;Bennett WF;Tieleman DP
氨基酸侧链从水分配到细胞膜的自由能是了解和预测膜蛋白稳定性、了解膜蛋白功能的关键参数之一。跨膜片段通常是非常疏水的，但可能含有对蛋白质的结构或功能重要的亲水残基。实验和理论研究表明，ASN等极性残基的存在会导致螺旋聚集体的形成(Stockner等人，2004年；Tatko等人，2006年)。电压门控钾通道KvAP(酱等，2003a)和KV1的晶体结构。2(Long等人，2005年)在离子通道界引起了激烈的辩论，因为一些基于晶体结构提出的模型会使精氨酸门控电荷暴露在脂质环境中(酱等人，2003b)。在KvAP晶体结构发表后，有人争辩说，在脂质暴露的环境中放置精氨酸几乎是不可能的，而且这种模型的激活能太高而不现实(Grabe等人，2004年)。然而，最近的一项实验研究表明，包含门控电荷的KvAP的S4片段能够以边缘稳定的跨膜螺旋的形式插入膜(Hessa等人，2005b)。目前，我们对氨基酸在脂双层中的分配行为了解有限。使用各种模型系统已经得出了许多实验标度，这些实验的结果被证明在预测膜蛋白的稳定性方面非常有用。在本期中，怀特、沃尔芬登和冯·海涅的观点概述了几个实验尺度，并讨论了它们对理解膜环境的重要性。分子动力学(MD)计算机模拟提供了侧链分配的补充视图，提供了实验无法获得的详细程度。我们最近对20个氨基酸中的17个氨基酸(不包括Pro、Gly和His)的分布进行了系统的计算(未发表的数据)。在这里，我们将把这些模拟的结果与几个实验规模进行比较。计算结果我们将重点关注我们最近工作的结果。在沃尔芬登的实验研究之后(见本期的透视图)，我们模拟了氨基酸侧链的小分子类似物。侧链在β-Carbon处被截断，α-Carbon被质子取代。例如，苯丙氨酸变成甲苯，异亮氨酸变成丁烷。为简单起见，我们将用相应氨基酸的三个字母代码来指代化合物。模拟是在一个含有脂分子、2,804个水分子和两个侧链的体系上进行的。采用伞形取样方案来确定脂双分子层中侧链的平均作用力。对每个残基总共进行了37次模拟，每次模拟的最小长度为30 ns，每个残基总共有1.1μS。对于一些残基，如Trp和Arg，为了提高计算精度，将模拟扩展到80 ns。根据计算的自由能分布，我们确定了两个尺度：一个用于膜中心，一个用于界面区域，总结如表I。图1A显示了部分密度分布，表明了各种脂质官能团的位置；图1B显示了带电形式和中性形式的Arg的平均作用力(PMF)的势。脂肪族残基(Ala、Val、Leu、Ile)对两个…都有利地分配
The free energy of partitioning an amino acid side chain from water into the cell membrane is one of the critical parameters for understanding and predicting membrane protein stability, and understanding membrane protein function. Transmembrane segments are generally very hydrophobic, but may contain hydrophilic residues that are important for the structure or function of the protein. Experimental and theoretical studies have shown that the presence of polar residues, such as Asn, can lead to the formation of helical aggregates (Stockner et al., 2004; Tatko et al., 2006). The crystal structures of the voltage-gated potassium channels KvAP (Jiang et al., 2003a) and Kv1. 2 (Long et al., 2005) have caused vigorous debate in the ion channel community as some models proposed based on the crystal structures would have the arginine gating charges exposed to the lipid environment (Jiang et al., 2003b). After the publication of the KvAP crystal structure, it was argued that it was next to impossible to put an arginine in a lipid-exposed environment, and that the activation energy for such a model would be far too high to be realistic (Grabe et al., 2004). However, a recent experimental study has shown that the S4 segment of KvAP, which contains the gating charges, is able to insert into the membrane as a marginally stable transmembrane helix (Hessa et al., 2005b). We currently have a limited understanding of the partitioning behavior of amino acids into lipid bilayers. Numerous experimental scales have been derived using a variety of model systems and the results of such experiments have proven very useful in the prediction of membrane protein stability. The Perspectives from White, Wolfenden, and von Heijne in this issue outline several experimental scales and discuss their importance for understanding the membrane environment. Molecular dynamics (MD) computer simulations provide a complementary view of side chain partitioning, providing a level of detail that is not accessible to experiment. We have recently performed a systematic set of calculations (unpublished data) on the distributions of 17 of 20 amino acids (Pro, Gly, and His excluded). Here, we will compare the results of these simulations to several experimental scales.Computational Results We will focus on the results of our recent work. Following Wolfenden’s experimental studies (see Perspective in this issue), we simulated small molecule analogues of the amino acid side chains. The side chains were truncated at the β-carbon with the α-carbon replaced by a proton. For example, phenylalanine becomes toluene, and isoleucine becomes butane. For simplicity, we will refer to the compounds by the three-letter code of the corresponding amino acid. Simulations were performed on a system containing 64 lipid molecules, 2,804 water molecules, and two side chains. An umbrella sampling protocol was employed to determine the potential of mean force for the side chain in the lipid bilayer. A total of 37 simulations were performed for each residue, with each simulation having a minimum length of 30 ns, for a total of 1.1 μs per residue. For some residues, such as Trp and Arg, the simulations were extended up to 80 ns in order to improve the accuracy of the calculation. Based on the calculated free energy profiles we have determined two scales: one for the center of the membrane and one for the interfacial region, summarized in Table I. Fig. 1 A shows a partial density profile, indicating the location of various lipid functional groups; Fig. 1 B shows the potential of mean force (PMF) for the charged and neutral forms of Arg. The aliphatic residues (Ala, Val, Leu, Ile) partition favorably to both the …
登录
查看更多内容
影响因子：
--
作者：
Aliste MP;Tieleman DP
通讯作者：
Tieleman DP
影响因子：
64.8
作者：
Jiang, YX;Ruta, V;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
56.9
作者：
Long, SB;Campbell, EB;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
3.4
作者：
Norman, Kristen E.;Nymeyer, Hugh
通讯作者：
Nymeyer, Hugh
DOI：
10.1073/pnas.0507618102
发表时间：
2005-10-18
影响因子：
11.1
作者：
Freites, JA;Tobias, DJ;White, SH
通讯作者：
White, SH