Exploring beta-sheet structure and interactions with chemical model systems.
Exploring beta-sheet structure and interactions with chemical model systems.
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DOI：
10.1021/ar800064f
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发表时间：
2008-10
影响因子：
18.3
通讯作者：
Nowick, James S.
中科院分区：
文献类型：
--
作者：
Nowick, James S.
“我不能创造的东西，我不理解。-Richard P. Feynman β-Sheets由通过氢键网络连接的延伸多肽链（β链）组成，广泛存在于蛋白质中。虽然β-折叠在蛋白质折叠结构中的重要性早已被认识到，但越来越多的人认识到β-折叠之间分子间相互作用的重要性。β-折叠的氢键边缘之间的分子间相互作用构成了生物分子识别的基本形式（如DNA碱基配对），并且涉及蛋白质四级结构、蛋白质-蛋白质相互作用以及肽和蛋白质聚集。β-折叠相互作用在生物过程中的重要性使其成为艾滋病、癌症和阿尔茨海默氏症等疾病干预的潜在靶点。这个帐户描述了我的研究小组使用化学模型系统来研究β-折叠的结构和相互作用。化学模型系统提供了一个很好的工具来探索β折叠，因为它们比蛋白质更小，更简单，更容易操作。合成化学模型还提供了控制或调节自然系统或开发其他有用应用的机会，并可能最终导致治疗疾病的新药。在我们的“人工β-折叠”中，分子模板和转角单元与肽结合以模拟平行和反平行β-折叠的结构。模板和转角单元与肽基团形成折叠的氢键结构，并有助于防止形成复杂的、不明确的聚集体。事实证明，复制肽β链一个边缘的氢键模式同时封闭另一个边缘的模板在防止聚集体形成和促进简单单体和二聚体结构的形成方面特别有价值。呈现暴露的氢键边缘的人工β-折叠可以形成明确定义的氢键二聚体。二聚化在氯仿溶液中容易发生，但在水溶液中需要额外的疏水相互作用。侧链之间的相互作用以及主链之间的氢键在二聚体形成中是重要的。人工β-折叠的NMR研究已经阐明了氢键互补性、尺寸互补性和手性互补性在这些相互作用中的重要性。这些配对偏好证明了β-折叠之间分子识别的序列选择性。这些研究有助于说明肽和蛋白质中β折叠之间分子间边对边相互作用的重要性。最终，这些模型系统可能会导致控制β-折叠相互作用和治疗疾病的新方法。
“What I cannot create, I do not understand. ” —Richard P. Feynman β-Sheets consist of extended polypeptide strands (β-strands) connected by a network of hydrogen bonds and occur widely in proteins. Although the importance of β-sheets in the folded structures of proteins has long been recognized, there is a growing recognition of the importance of intermolecular interactions among β-sheets. Intermolecular interactions between the hydrogen-bonding edges of β-sheets constitute a fundamental form of biomolecular recognition (like DNA base pairing) and are involved protein quaternary structure, protein-protein interactions, and peptide and protein aggregation. The importance of β-sheet interactions in biological processes makes them potential targets for intervention in diseases such as AIDS, cancer, and Alzheimer’s. This Account describes my research group’s use of chemical model systems to study the structure and interactions of β-sheets. Chemical model systems provide an excellent vehicle with which to explore β-sheets, because they are smaller, simpler, and easier to manipulate than proteins. Synthetic chemical models also provide the opportunity to control or modulate natural systems or to develop other useful applications and may eventually lead to new drugs with which to treat diseases. In our “artificial β-sheets”, molecular template and turn units are combined with peptides to mimic the structures of parallel and antiparallel β-sheets. The templates and turn units form folded, hydrogen-bonded structures with the peptide groups and help prevent the formation of complex, ill-defined aggregates. Templates that duplicate the hydrogen-bonding pattern of one edge of a peptide β-strand while blocking the other edge have proven particularly valuable in preventing aggregate formation and in promoting the formation of simple monomeric and dimeric structures. Artificial β-sheets that present exposed hydrogen-bonding edges can form well-defined hydrogen-bonded dimers. Dimerization occurs readily in chloroform solutions but requires additional hydrophobic interactions to occur in aqueous solution. Interactions among the side chains, as well as hydrogen bonding among the main chains, are important in dimer formation. NMR studies of artificial β-sheets have elucidated the importance of hydrogen-bonding complementarity, size-complementarity, and chiral complementarity in these interactions. These pairing preferences demonstrate sequence selectivity in the molecular recognition between β-sheets. These studies help illustrate the importance of intermolecular edge-to-edge interactions between β-sheets in peptides and proteins. Ultimately, these model systems may lead to new ways of controlling β-sheet interactions and treating diseases in which they are involved.
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