Role of water in protein aggregation and amyloid polymorphism.
Role of water in protein aggregation and amyloid polymorphism.
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DOI：
10.1021/ar2000869
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发表时间：
2012-01-17
影响因子：
18.3
通讯作者：
Straub, John E.
中科院分区：
文献类型：
--
作者：
Thirumalai, D.;Reddy, Govardhan;Straub, John E.
寡聚体和淀粉样纤维与各种神经退行性疾病之间的联系提高了破译蛋白质聚集原理的必要性。体内淀粉样蛋白的形成机制涉及多个辅助子和与膜的复杂相互作用。然而，人们认为，在明确的系统中了解体外淀粉样蛋白形成的生物物理基础，对于发现优先与具有淀粉样蛋白生成倾向的区域结合的配体是重要的。各种多肽原纤维结构的确定为利用计算机模拟探索低聚物形成和淀粉样蛋白生长的动力学奠定了基础。大多数实验和模拟研究主要是从蛋白质的角度进行解释，而没有太多地考虑溶剂在促进或抑制寡聚体形成和组装到原丝和淀粉样纤维中的作用。在这里，我们提供了一个观点，即与水的相互作用如何影响Aβ单体的折叠景观，Aβ16-22片段中低聚物的形成，以及酵母Pron Sup35多肽中原丝的形成。这些体系的显式分子动力学模拟阐明了水如何控制高阶结构的自组装，并为理解齐聚物和原纤维生长的动力学提供了结构基础。模拟结果表明，Aβ-肽的单体具有许多紧密的构象。具有盐桥的易于聚集的结构(N*)与原纤维中的多肽结构具有惊人的相似性，需要克服高度的解溶障碍。一般来说，N*结构没有显著填充的序列不太可能聚集。一般情况下，齐聚物和纤维在两个步骤中形成。在第一阶段，水从富含疏水残基的多肽(例如Aβ16-22)之间的区域排出，导致无序低聚物。在第二阶段，多肽沿优先轴排列，形成具有反平行β链排列的有序结构。有序组装体中的限速步骤是在限制体积内重排多肽。从酵母蛋白的两个片层相互堆积形成干燥界面的极性多肽片段中形成原丝的机制表明，水极大地减缓了自组装速度。当薄片相互靠近时，两条完美有序的一维水线通过氢键稳定到极性侧链的酰胺基团，导致形成长寿命的亚稳态结构。从毛孔中释放被困住的水会形成螺旋状的、具有干燥界面的原丝。类似地，将溶剂化单体添加到预制原纤维中的驱动力是水的释放，水的熵增加和有利的肽间氢键的形成弥补了多肽的熵损失。我们认为，两步机制，一个也用于蛋白质结晶的模型，必须适用于更高阶淀粉样蛋白结构的形成。在第一步，一个富含含有N*结构的蛋白质的液滴形成。多肽的构象重排导致有序状态发生在液滴内，通过单体掺入或与其他液滴碰撞，最终导致β-淀粉样蛋白的形成。因为存在一个具有不同水含量的不同N*结构的系综，所以一定有许多不同的富含水的多态结构。提出了支持这一建议的证据。水扮演着多种角色，在以疏水为主的序列的情况下，它加速了纤维的形成。相反，水稳定的亚稳中间体大大减缓了纤维在亲水序列中的生长速度。
The link between oligomers and amyloid fibrils and a variety of neurodegenerative diseases raises the need to decipher the principles governing protein aggregation. Mechanisms of in vivo amyloid formation involve a number of coconspirators and complex interactions with membranes. Nevertheless, it is believed that understanding the biophysical basis of in vitro amyloid formation in well-defined systems is important in discovering ligands that preferentially bind to regions that harbor amyloidogenic tendencies. Determination of structures of fibrils of a variety of peptides has set the stage for probing the dynamics of oligomer formation and amyloid growth using computer simulations. Most experimental and simulation studies have been interpreted largely from the perspective of proteins without much consideration of the role of solvent in enabling or inhibiting oligomer formation and assembly to protofilaments and amyloid fibrils. Here, we provide a perspective on how interactions with water affect folding landscapes of Aβ monomers, oligomer formation in Aβ16–22 fragment, protofilament formation in a peptide from yeast prion Sup35. Explicit molecular dynamics simulations of these systems illustrate how water controls the self-assembly of higher order structures and provide a structural basis for understanding the kinetics of oligomer and fibril growth. Simulations show that monomers of Aβ-peptides sample a number of compact conformations. Population of aggregation-prone structures (N*) with salt-bridge, which bear a striking similarity to the peptide structure in the fibril, requires overcoming a high desolvation barrier. In general, sequences for which N* structures are not significantly populated are unlikely to aggregate. Generically oligomers and fibrils form in two steps. In the first stage water is expelled from the region between peptides rich in hydrophobic residues (for example Aβ16–22) resulting in the disordered oligomers. In the second stage, the peptides align along a preferred axis to form ordered structures with anti-parallel β-strand arrangement. The rate limiting step in the ordered assembly is the rearrangement of the peptides within a confining volume. The mechanism of protofilament formation in a polar peptide fragment from the yeast prion in which the two sheets are packed against each other creating a dry interface illustrates that water dramatically slows down self-assembly. As the sheets approach each other two perfectly ordered one-dimensional water wires, which are stabilized by hydrogen bonds to the amide groups of the polar side chains, results in the formation of long-lived metastable structures. Release of the trapped water from the pore creates a helically-twisted protofilament with a dry interface. Similarly, the driving force for addition of a solvated monomer to a preformed fibril is the release of water whose entropy gain and favorable inter peptide hydrogen bond formation compensates for loss in entropy of the peptides. We suggest that the two-step mechanism, a model also used in protein crystallization, must hold good for higher order amyloid structure formation. In the first step a liquid droplet rich in proteins containing N* structures form. Conformational rearrangement of the peptides leading to an ordered state occurs within the droplet by incorporation of monomers or collision with other droplets and ultimately results in β-amyloid formation. Because there is an ensemble of distinct N* structures with varying water content there must be a number of distinct water-laden polymorphic structures. Evidence for this proposal is presented. Water plays multifarious roles, which in the case of predominantly hydrophobic sequences, accelerates fibril formation. In contrast, water-stabilized metastable intermediates dramatically slow down fibril growth rates in hydrophilic sequences.
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DOI：
10.1126/science.1173155
发表时间：
2009-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maji SK;Perrin MH;Sawaya MR;Jessberger S;Vadodaria K;Rissman RA;Singru PS;Nilsson KP;Simon R;Schubert D;Eisenberg D;Rivier J;Sawchenko P;Vale W;Riek R
通讯作者：
Riek R
DOI：
10.1073/pnas.0911107107
发表时间：
2010-05-04
影响因子：
11.1
作者：
Mao, Albert H.;Crick, Scott L.;Pappu, Rohit V.
通讯作者：
Pappu, Rohit V.
影响因子：
8.6
作者：
Li, Mai Suan;Co, Nguyen Truong;Thirumalai, D.
通讯作者：
Thirumalai, D.
影响因子：
--
作者：
Auer, Stefan;Dobson, Christopher M.;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele
影响因子：
2.9
作者：
JAENICKE, R;LAUFFER, MA
通讯作者：
LAUFFER, MA