Exploring interactions of polar fluoroaliphatic motifs with biomolecules.

该项目将探索两种新型有机氟基序的性质和应用，这两种基序是从理解部分氟化共聚物具有特别的极性而产生的。这些部分氟化基序可以与超疏水的氟化全氟化碳以及非极性和疏水的碳氢化合物形成对比。这些类别的化合物也具有化学持久性，例如PFAS，并且存在与其在环境中积累相关的担忧。它出现了一个中间的情况与氟甲基（-CH 2 F）或氟亚甲基（-CHF-）产生的化合物具有更大的亲和力，对水和更容易生物降解和改善的环境性能。该计划选择了两个这样的图案进行调查，是与生物活性物质发现或作为化学生物学工具相关的各种情况。这些是Janus面环己烷，其在环周围具有氟亚甲基（-CHF），特别是在环的一面上具有氟而另一面上具有氢的立体化学排列中，因为这提供了最大的极性。第二个是未开发的叔丁基三氟基序（TBTF），它改变了叔丁基的高度疏水性，使其更具亲水性。该方案分为三个工作包（WP）。WP-1将研究W-肽类似物的结合，W-肽是一种重要受体（FPR 2）的高亲和力激动剂，与从心脏病到阿尔茨海默病的一系列疾病相关。W-肽与受体的相互作用被很好地表征。这些新的基序将被放置到W-肽的特定侧链中，以评估相对功效并探索与受体的结合相互作用，作为理解它们在蛋白质活性位点中相互作用的手段。WP-2将采用表面科学方法，使用原子力显微镜（AFM）来评估表面和涂覆在以有机氟基序终止的分子单层中的悬臂尖端的相互作用。设计了广泛的实验来探索与极性取代基（例如RCO 2-，RN 4+）的相互作用的强度和基序本身之间的相互作用的强度，以及这些相互作用在不同离子溶液中的影响。这项研究将扩展到探索双链和单链DNA和DNA的相互作用强度。本WP旨在了解在生物化学中广泛发现的基序和分子之间的相互作用。WP-3将非常特异性地延伸到核酸，并建立在Janus面环己烷似乎与双链DNA非常强烈地相互作用而与单链DNA的相互作用要小得多的观察基础上。这些研究将使用荧光显微镜检测单分子-分子相互作用的技术进行探索。我们将探索是否可以通过增加基序的数量（亲合力）来加强相互作用，或者是否可以将两个或更多个dsDNA分子附着到具有几个Janus面基序的探针上（交联），本质上是在纳米级上操纵dsDNA，应用扩展到对接货物到双链DNA的特定功能，如剪接和交联等。本WP还将探索与有机氟基序的相互作用，G-四链体DNA，另一种在细胞周期和程序性细胞死亡（凋亡）中具有重要意义的DNA形态，其控制在治疗癌（永生）细胞中具有意义。我们将用我们的有机氟基序修改已建立的G-四链体分子（候选药物），并通过X射线晶体学和一系列生物物理技术研究它们的相互作用。在该计划的最后，我们的目标是提供新的工具和知识，这应该有助于下一代治疗和诊断在医疗保健的发展。

The project will explore the properties and applications of two novel organo-fluorine motifs which have emerged from an understanding that partially fluorinated aliphatics have particularly polar properties.These partially fluorinated motifs can be contrasted with super hydrophobic fluorinated perfluorcarbons, and also hydrocarbons which are nonpolar and also hydrophobic. These classes of compounds are also chemically persistent eg PFASs, and there are concerns associated with their accumulation in the environment. It emerges that an intermediate situation with fluoromethyl (-CH2F) or fluoromethylene (-CHF-) generate compounds have a much greater affinity for water and are much more susceptible to biodegradation and improved environmental performance. This programme selects two such motifs for investigation is a variety of circumstances associated with bio-actives discovery or as tools in chemical biology. These are Janus face cyclohexanes which have fluoromethylene groups (-CHF) around the ring, and particularly in a stereochemical arrangement that has the fluorines on one face of the ring and hydrogens on the other, as this offers maximum polarity. The second is the unexplored tert-buty-trifluoro motif (TBTF) which transforms the highly hydrophobic properties of a tert-butyl group and renders it much more hydrophilic. The programme is arranged into three work-packages (WPs). WP-1 will investigate the binding of analogues of the W-peptide, a high affinity agonist of an important receptor (FPR2) associated with a range of disorders extending from heart disease to Alzheimers. The interaction of W-peptide with the receptor is very well characterised. These novel motifs will be placed into specific side chains of the W-peptide to assess relative efficacy and explore binding interactions with the receptor as a means to understanding their interactions in a protein active site. WP-2 will take a surface science approach using Atomic Force Microscopy (AFM) to assess the interactions of surfaces and cantilever tips coated in monolayers of molecules terminated with the organofluorine motifs. A wide range of experiments is designed to explore the strength of interactions with polar substituents (eg RCO2-, RN4+) and the strength of interactions between the motifs themselves, and how those interactions are influenced in different ionic solutions. The study will extend to exploring the strength of interactions with double- and single- stranded DNA and DNA. This WP aims to understand interactions between the motifs and molecules found widely in biochemistry. WP-3 will extend very specifically to nucleic acids and builds on an observation that the Janus face cyclohexanes appear to interact very strongly with double stranded DNA and much less so with single stranded DNA. These studies will be explored using techniques which can detect single molecule-molecule interactions using fluorescence microscopy. We will explore if the interactions can be strengthened by increasing the number of motifs (avidity) or if two or more molecules of dsDNA will attach to one probe with several Janus face motifs (crosslinking), essentially manipulating dsDNA on the nanoscale, with applicatiosn extending to docking cargo to dsDNA for specific functions such as splicing and cross linking etc. This WP will also explore interactions with the organofluorine motifs on G-quadruplex DNA, another DNA morphology which is of great significance in the cell cycle and programmed cell death (apoptosis), the control of which has implications in treating cancerous (immortal) cells. We will modify established G-quadruplex molecules (drug candidates) with our organofluorine motifs and examine their interactions by X-ray crystallography and a range of biophysical techniques. At the end of the programme we aim to deliver new tools and knowledge which should contribute to the development of next generation therapeutics and diagnostics in healthcare.