Controlling the morphology of cross β-sheet assemblies by rational design
Controlling the morphology of cross β-sheet assemblies by rational design
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DOI：
10.1021/ja050558c
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发表时间：
2005-06-15
影响因子：
15
通讯作者：
Kelly, JW
中科院分区：
文献类型：
--
作者：
Deechongkit, S;Powers, ET;Kelly, JW
具有简单两亲性序列的低分子量肽模拟物可以帮助阐明交叉β-折叠组装体的结构，例如淀粉样蛋白原纤维。本文所述的肽模拟物包含二苯并呋喃模板、由交替的亲水性和疏水性残基组成的两条肽链和羧基末端，其中每一个可以变化以探测β-折叠自组装过程的结构要求。二苯并呋喃模板将链定位在大约10埃的位置，允许链中相应的疏水侧链包装成塌陷的U形结构。这种构象通过疏水相互作用而不是分子内氢键来稳定。通过分子间氢键和疏水相互作用实现的塌陷的肽模拟物的分子间堆叠提供了具有交叉β-折叠结构的25-27埃宽的原丝。由二苯并呋喃亚结构介导并由疏水效应驱动的原丝的缔合提供50-60埃宽的丝。这些宽度可以通过改变肽链的长度来控制。可以通过改变模板、C-末端和缓冲离子组成来控制纤丝进一步组装成原纤维或带。
Low molecular weight peptidomimetics with simple amphiphilic sequences can help to elucidate the structures of cross beta-sheet assemblies, such as amyloid fibrils. The peptidomimetics described herein comprise a dibenzofuran template, two peptide strands made up of alternating hydrophilic and hydrophobic residues, and carboxyl termini, each of which can be varied to probe the structural requirements for beta-sheet self-assembly processes. The dibenzofuran template positions the strands approximately 10 angstrom apart, allowing corresponding hydrophobic side chains in the strands to pack into a collapsed U-shaped structure. This conformation is stabilized by hydrophobic interactions, not intramolecular hydrogen bonds. Intermolecular stacking of the collapsed peptidomimetics, enabled by intermolecular hydrogen bonding and hydrophobic interactions, affords 25-27 angstrom wide protofilaments having a cross beta-sheet structure. Association of protofilaments, mediated by the dibenzofuran substructures and driven by the hydrophobic effect, affords 50-60 angstrom wide filaments. These widths can be controlled by changing the length of the peptide strands. Further assembly of the filaments into fibrils or ribbons can be controlled by modification of the template, C-terminus, and buffer ion composition.