Institute of Chemistry and Biochemistry - Organic Chemistry, Freie Universität Berlin , Takustrasse 3, 14195 Berlin, Germany.
Institute of Chemistry, Technische Universität Berlin , Müller-Breslau-Str. 10, 10623 Berlin Germany.
Acc Chem Res. 2017 Sep 19;50(9):2093-2103. doi: 10.1021/acs.accounts.7b00226. Epub 2017 Aug 12.
Deciphering the fluorine code is how we describe not only the focus of this Account, but also the systematic approach to studying the impact of fluorine's incorporation on the properties of peptides and proteins used by our groups and others. The introduction of fluorine has been shown to impart favorable, but seldom predictable, properties to peptides and proteins, but up until about two decades ago the outcomes of fluorine modification of peptides and proteins were largely left to chance. Driven by the motivation to extend the application of the unique properties of the element fluorine from medicinal and agro chemistry to peptide and protein engineering we have established extensive research programs that enable the systematic investigation of effects that accompany the introduction of fluorine into this class of biopolymers. The introduction of fluorine into amino acids offers a universe of options for modifications with regard to number and position of fluorine substituents in the amino acid side chain. Moreover, it is important to emphasize that the consequences of incorporating the C-F bond into a biopolymer can be attributed to two distinct yet related phenomena: (i) the fluorine substituent can directly engage in intermolecular interactions with its environment and/or (ii) the other functional groups present in the molecule can be influenced by the electron withdrawing nature of this element (intramolecular) and in turn interact differently with their immediate environment (intermolecular). Based on our studies, we have shown that a change in number and/or position of as subtle as one single fluorine substituent has the power to considerably modify key properties of amino acids such as hydrophobicity, polarity, and secondary structure propensity. These properties are crucial factors in peptide and protein engineering, and thus, fluorinated amino acids can be applied to fine-tune properties such as protein folding, proteolytic stability, and protein-protein interactions provided we understand and become able to predict the outcome of a fluorine substitution in this context. With this Account, we attempt to analyze information we gained from our recent projects on how the nature of the fluorine atom and C-F bond influence four key properties of peptides and proteins: peptide folding, protein-protein interactions, ribosomal translation, and protease stability. These results impressively show why the introduction of fluorine creates a new class of amino acids with a repertoire of functionalities that is unique to the world of proteins and in some cases orthogonal to the set of canonical and natural amino acids. Our concluding statements aim to offer a few conserved design principles that have emerged from systematic studies over the last two decades; in this way, we hope to advance the field of peptide and protein engineering based on the judicious introduction of fluorinated building blocks.
破译氟码不仅描述了本文的重点，也是我们研究氟原子掺入对肽和蛋白质性质影响的系统方法。引入氟原子可以赋予肽和蛋白质有利但很少可预测的性质，但直到大约二十年前，肽和蛋白质的氟修饰的结果在很大程度上还只能靠运气。受将氟元素的独特性质从药物和农业化学扩展到肽和蛋白质工程应用的动机的驱动，我们已经建立了广泛的研究计划，使我们能够系统地研究在这一类生物聚合物中引入氟原子时伴随的影响。在氨基酸中引入氟原子为修饰提供了广泛的选择，包括在氨基酸侧链中氟取代基的数量和位置。此外，重要的是要强调，将 C-F 键引入生物聚合物的后果可以归因于两个截然不同但相关的现象：(i) 氟取代基可以直接与环境中的其他分子相互作用，或者 (ii) 分子中存在的其他官能团可以受到该元素的电子吸电性的影响（分子内），并反过来与它们的直接环境（分子间）以不同的方式相互作用。根据我们的研究，我们已经表明，即使是一个微小的氟取代基数量和/或位置的变化，也有能力极大地改变氨基酸的关键性质，如疏水性、极性和二级结构倾向。这些性质是肽和蛋白质工程的关键因素，因此，只要我们了解并能够预测在这种情况下氟取代的结果，氟代氨基酸就可以用于微调蛋白质折叠、蛋白酶稳定性和蛋白质-蛋白质相互作用等性质。本文试图分析我们最近在氟原子和 C-F 键的性质如何影响肽和蛋白质的四个关键性质的项目中获得的信息：肽折叠、蛋白质-蛋白质相互作用、核糖体翻译和蛋白酶稳定性。这些结果令人印象深刻地展示了为什么引入氟原子创造了一类新的氨基酸，它们具有独特的官能团，这在蛋白质世界中是独一无二的，在某些情况下与经典和天然氨基酸的功能是正交的。我们的结论旨在提供一些从过去二十年的系统研究中得出的保守设计原则；通过这种方式，我们希望基于明智地引入氟化构建块来推进肽和蛋白质工程领域。
