Bottom up Synthesis of Complex Biological Model Systems

为了解决诸如“生命起源于什么形式？”这样的问题。以及‘对复杂的、逼真的行为有什么要求？’弗莱彻小组已经开发出能够自我复制的化学系统。这使得我们可以探索一个最小的系统是否可以模仿我们在生活中看到的模式和行为，以及哪些特定的设计特征会产生哪些现象。就像今天在生物体中看到的DNA复制的力量一样，有一些广泛的共识，即自我复制的概念可能是解开益生元情景中的复杂性和进化的关键。1，2为此，一些对益生元化学感兴趣的团体已经开发出能够划分和生长的新的化学系统，每个系统的核心都有自复制的概念。3，4我们目前的方法依赖于反应物的相分离来提供一定程度的有序性，很像细胞内代谢活动的定位。发生在界面上的反应可以受到正反馈机制的影响，前提是该反应改变了界面的某些属性，如表面积。在我们的案例中，这种效果是通过Morrow和同事建立的硫醇-二硫键交换反应实现的。6这涉及疏水(1)和亲水(2)反应伙伴的相互作用，如图1所示，瞬时形成不稳定的胶束表面活性剂产品4，其数量通过添加化学氧化剂维持。这项工作体现了类生命系统的一个核心特征，即它们以动态稳定的状态存在，不断需要燃料以避免衰变。7最近的工作侧重于开发密切相关的复制因子，它们的形成速度、稳定性和氧化能力存在差异。这使得能够观察到不同物种之间的竞争和寄生行为，以及通过有氧氧化回收芳香硫醇3以维持燃料系统。使用替代的化学复制物，小组内的同事还将油滴的移动与表面活性剂的生产联系起来。8随着反应的进行，液滴上建立了表面张力梯度，导致推进剂流过其表面并产生内部对流电流(见图2)。这项工作展示了类生命实体的进一步性质，即原细胞液滴的分割和燃料的定向运动。项目目标和影响：未来的研究将旨在通过获得更丰富的数据来了解硫醇-二硫化物体系中复杂行为的原因，并确定导致观察到的模式的关键参数和物理化学步骤(例如，相转移)。在上述工作的基础上，我们还计划利用油滴中产生的内部对流来推动进一步的化学工作。通过在油滴中注入适当的试剂，我们可以预见对流电流可以促进二次化学反应，从而模拟一个简单的代谢序列，如可以想象到的涉及一个基本细胞器的序列。对这些主题的一种可能的扩展可能旨在将阶段分离的过程联系起来，最终产生一个相对复杂的自我复制因子池，成功地从简单的构建块导航到一条路线。这一目标的实现将是对生物进化中所见的选择和突变行为的直接类比。该项目属于EPSRC物理科学主题合成有机化学和化学反应动力学和机理，但其结果最终也可能在合成超分子化学和合成生物学领域产生影响。

In the pursuit to address questions such as 'In what form did life originate?' and 'What are the requirements for complex life-like behaviour?' the Fletcher group has developed chemical systems capable of self-replication. This allows the exploration of whether a minimal system can mimic the patterns and behaviours we see in life and which specific design features give rise to which phenomena. Just like the power of DNA replication seen in organisms today there is some widespread agreement that self-replication concepts could have been key to unlocking complexity and evolution in prebiotic scenarios.1,2 For this reason a number of groups interested in prebiotic chemistry have developed novel chemical systems able to compartmentalise and grow, each with the concept of self-replication at their core.3,4Our current approach relies upon the phase separation of the reactants to provide a degree of order, much like the localisation of metabolic activities within a cell. Reactions that occur across an interface can be subject to positive feedback mechanisms provided the reaction alters some property of the interface, such as surface area. In our case, this effect is achieved using a thiol-disulfide exchange reaction established by Morrow and coworkers.6 This involves the interaction of hydrophobic (1) and hydrophilic (2) reaction partners as depicted in Figure 1 to transiently form an unstable micellar surfactant product 4 whose population is sustained by the addition of a chemical oxidant. This work embodied a core feature of life-like systems in that they exist in a kinetically stabilised state, constantly requiring fuel to avoid decay.7 More recent work has focused on developing closely related replicators with differences in their formation rates, stabilities and ability to oxidise. This has allowed the observation of competition and parasitic-like behaviour between different species and the recycling of aromatic thiol 3 by aerobic oxidation to sustain a fuelled system.Using an alternative chemical replicator, coworkers within the group have also coupled the movement of oil droplets to the production of a surfactant.8 As the reaction proceeds, a surface tension gradient is established on the droplet resulting in the flow of propellant over its surface and the generation of internal convection currents (see Figure 2). This work demonstrated further properties of life-like entities, namely the partitioning of protocell droplets and fuelled directional movement.Project aims and impact:Future investigations will aim to understand the reasons for complex behaviour in the thiol-disulfide system by obtaining richer data and determine the key parameters and physicochemical steps (e.g. phase transfer) that give rise to the observed patterns. Building upon the prior work summarised above, we also aim to use the internal convection currents created within oil droplets to drive further chemical work. By the implantation of appropriate reagents within the oil droplet we envisage that the convection currents could promote a secondary chemical reaction thereby mimicking a simple metabolic sequence such as could conceivably be found involving a rudimentary organelle. One possible extension on these themes could aim to link phase separated processes, ultimately generating a pool of relatively complex self-replicators that were successful in navigating a route from simple building blocks. Achievement of this goal would be a direct analogy to the selection and mutation behaviour seen in biological evolution.This project falls within the EPSRC Physical Sciences themes of Synthetic Organic Chemistry and Chemical Reaction Dynamics and Mechanism however its outcomes may ultimately also have implications in the fields of Synthetic Supramolecular Chemistry and Synthetic Biology.