Tipping the Scale from Disorder to Alpha-helix: Folding of Amphiphilic Peptides in the Presence of Macroscopic and Molecular Interfaces.
Tipping the Scale from Disorder to Alpha-helix: Folding of Amphiphilic Peptides in the Presence of Macroscopic and Molecular Interfaces.
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将量表从疾病到α-螺旋中倾斜：在存在宏观和分子界面的情况下两亲性肽的折叠。
DOI：
10.1371/journal.pcbi.1004328
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发表时间：
2015-08
影响因子：
4.3
通讯作者：
Sayar M
中科院分区：
文献类型：
--
作者：
Dalgicdir C;Globisch C;Peter C;Sayar M
二级两亲性是蛋白质二级结构元素所固有的。通过相互之间形成有利的能量接触，这些两亲性的组成部分形成了三级结构。另一方面，小的蛋白质和肽通常太短，无法形成多个结构元素，也无法在内部稳定它们。因此，这些分子通常在结构上是不明确的，以至于在溶液中存在很大程度的内在无序。因此，它们的构象偏好特别容易受到环境条件的影响，如pH值、盐或界面的存在。在这项研究中，我们使用分子动力学模拟分析了两种合成肽LKKLLKLLKKLLKL （LK）和EAALAEALAEALAE （EALA）的构象行为，它们在形成α -螺旋时具有内置的二级两亲性。我们使用这些模型肽系统地研究了它们的聚集以及宏观和分子界面对它们的构象偏好的影响。我们发现肽既不是散装水中的随机线圈，也不是完全形成的α螺旋，而是采用多种构象和具有短寿命的二级结构元件。这为环境变化下的构象选择和种群迁移提供了依据。这些肽对宏观和分子界面（由聚集伙伴呈现）的反应差异可能与它们在散装水中固有的α -螺旋倾向有关。我们发现，多肽的聚集行为也受到界面存在与否的强烈影响，而微妙地取决于它们的表面电荷和疏水性。小蛋白和多肽具有重要的生物医学意义，它们具有穿透细胞、破坏细胞膜或形成潜在的神经毒性纤维聚集体的能力。这是相当有趣的，同一肽可以参与所有这些过程取决于它的环境。因此，了解环境如何引导肽从无序状态到α -螺旋或β -薄片是很重要的。通过计算机模拟研究两种不同的肽，我们发现这个谜题的一个线索是所谓的无序分子在水中的状态，它实际上是以大量部分折叠的短寿命构象为特征的。我们研究了与宏观界面的相互作用如何通过在其他构象上促进α -螺旋来影响这种多态构象集合。此外，我们表明，两肽的结合也可以被视为与界面-分子界面的相互作用。我们表明，宏观和分子界面的影响很大程度上取决于它们强制分配疏水和亲水残基的能力。当两个界面相互竞争时，当宏观分块与肽结合在一起时，这种效应就会变得更加微妙：相反力的相对平衡决定了聚合体的稳定性和结构。
Secondary amphiphilicity is inherent to the secondary structural elements of proteins. By forming energetically favorable contacts with each other these amphiphilic building blocks give rise to the formation of a tertiary structure. Small proteins and peptides, on the other hand, are usually too short to form multiple structural elements and cannot stabilize them internally. Therefore, these molecules are often found to be structurally ambiguous up to the point of a large degree of intrinsic disorder in solution. Consequently, their conformational preference is particularly susceptible to environmental conditions such as pH, salts, or presence of interfaces. In this study we use molecular dynamics simulations to analyze the conformational behavior of two synthetic peptides, LKKLLKLLKKLLKL (LK) and EAALAEALAEALAE (EALA), with built-in secondary amphiphilicity upon forming an alpha-helix. We use these model peptides to systematically study their aggregation and the influence of macroscopic and molecular interfaces on their conformational preferences. We show that the peptides are neither random coils in bulk water nor fully formed alpha helices, but adopt multiple conformations and secondary structure elements with short lifetimes. These provide a basis for conformation-selection and population-shift upon environmental changes. Differences in these peptides’ response to macroscopic and molecular interfaces (presented by an aggregation partner) can be linked to their inherent alpha-helical tendencies in bulk water. We find that the peptides’ aggregation behavior is also strongly affected by presence or absence of an interface, and rather subtly depends on their surface charge and hydrophobicity. Small proteins and peptides have important biomedical implications with their ability to penetrate cells, disrupt cell membranes, or form—potentially neurotoxic—fibrillar aggregates. It is rather intriguing that the same peptide can take part in all these processes depending on its environment. Hence it is important to understand how the environment guides the peptide from a disordered state to an alpha-helix or beta-sheet. By studying two different peptides with computer simulations, we find that one clue to this puzzle is the state of the allegedly disordered molecule in water, which is in fact characterized by a vast number of partially folded short-lived conformations. We investigate how interaction with macroscopic interfaces affects this multi-state conformational ensemble by promoting an alpha-helix over the other conformers. Furthermore, we show that association of two peptides can also be viewed as an interaction with an interface—a molecular interface. We show that the impact of macroscopic and molecular interfaces strongly depends on their ability to enforce partitioning of hydrophobic and hydrophilic residues. The effect gets more subtle as soon as macroscopic partitioning is coupled with peptide association where two interfaces compete: the relative balance of opposing forces determines aggregate stability and structure.