An integrated molecular simulation, biophysical experimentation and toxicology bioassay approach for mechanistic understanding of toxic effects of ionic liquids

主要研究者： Jindal Shah提案编号： 1134238本研究的主要目标是了解离子液体（一种新兴的工业溶剂）毒性的分子水平机制，以及这些机制如何在系统水平上表现出来，从而导致对给定生物体的毒性。 拟议的研究将由尚未证实的假设指导，即离子液体直接与磷脂双层相互作用，从而损害膜的完整性。 一个由生物学家、化学工程师和分子建模师组成的跨学科团队将在这个项目上合作。 将进行毒理学生物测定实验以确定相对于对照导致微生物生长减少50%的离子液体浓度EC 50。 单分子光谱和成像实验将用于确定模型脂质双层在EC 50浓度附近的形态和动力学。 先进的分子动力学模拟将在相同的浓度下进行，以量化结构和动力学量的脂质双层沿着与分子水平的运动的双层的细节。 模拟也将被用来确定在脂质双层界面的离子液体物种的结构和动力学，信息是很难获得实验。 将对两种类型的生物进行毒理学生物测定研究：莱茵衣藻和大肠杆菌。 中性脂质双层和带负电荷的脂质双层将作为模型生物膜。 两个非常不同的类的离子液体将被调查。 第一组离子液体将基于具有不同烷基链长度的1-烷基-3-甲基咪唑鎓阳离子与阴离子配对，例如氯离子和双三氟甲基磺酰亚胺，其已经被非常详细地研究并且可能被大量制造。 第二组离子液体将由具有类似阴离子的阳离子四丁基鏻组成。 这些离子液体和它们的变体比基于咪唑的离子液体毒性更小，并且目前正在研究作为潜在的CO2捕获溶剂。这项工作的灵感来自于这样一个事实，即离子液体定义为纯盐，在环境条件下是液体？已经成为一系列技术应用的有前途的新溶剂，包括气体分离、润滑、电池和治疗剂。 学术界和工业界对离子液体研究的爆炸式增长，加上工业界采用离子液体的可能性越来越大，导致迫切需要了解这些材料在其命运，运输和对生物体的毒性方面对环境的影响。 大量的毒性生物测定研究表明，烷基链长、阴离子类型和亲脂性都在离子液体毒性中起作用。 然而，缺乏对这些因素如何导致毒性以及如何操纵它们以实现离子液体的期望毒性特性的基本分子水平的理解。 为了解决这一关键的知识差距，提出的链接分子模拟，生物物理实验和毒性生物测定方法是非常有前途的，因为它将导致更大的机制理解离子液体毒性比可能通过单独的一种技术。虽然拟议的研究针对两类离子液体，但所获得的基本理解具有广泛的意义，可以整合到毒性较小的离子液体的合理设计中，这将导致化学工艺和产品的开发，减少环境足迹。 这项工作也有利于目前的努力，旨在利用离子液体的治疗性能，其中离子液体与脂质双层的相互作用的知识是至关重要的。 该研究将提供有关细胞膜特性的基本信息，这些特性决定了对离子液体破坏的敏感性，这最终可能使能够在细胞内运输离子液体的微生物工程化，以生物降解离子液体。 这项研究的另一个主要目标是教和训练学生如何通过在跨学科的实验/计算环境中工作，在分子水平的相互作用和这种相互作用在系统水平上的表现之间建立智力联系。 从代表性不足的群体中招募妇女和学生的努力将遵循PI？的行之有效的方法，并将建立在几个现有的计划在圣母院。 计划通过圣母院公共事务办公室向更广泛的受众广泛传播这一活动的成果

PI: Jindal ShahProposal Number: 1134238The primary goal of this research is to understand the molecular level mechanisms of toxicity of ionic liquids, an emerging class of industrial solvents, and how such mechanisms manifest at a systems level to result in toxicity to a given organism. The proposed research will be guided by the as-yet unproven hypothesis that ionic liquids directly interact with the phospholipid bilayer and thereby compromise membrane integrity. An interdisciplinary team of biologists, chemical engineers, and molecular modelers will collaborate on this project. Toxicological bioassay experiments will be carried out to determine the ionic liquid concentrations EC50 that cause a 50% reduction in growth of microbes relative to a control. Single molecule spectroscopy and imaging experiments will be used to determine the morphology and dynamics of model lipid bilayers around the EC50 concentrations. Advanced molecular dynamics simulations will be carried out at the same concentrations to quantify structural and dynamical quantities for the lipid bilayer along with details on the molecular-level motion of the bilayer. The simulations will also be used to determine the structure and dynamics of ionic liquid species at the lipid bilayer interface, information that is difficult to obtain experimentally. Two types of organisms will be studied for toxicological bioassays: the alga Chlamydomonas reinhardtii and the bacterium Escherichia coli. A neutral-lipid bilayer and a negatively-charged lipid bilayer will serve as model organism membranes. Two very different classes of ionic liquids will be investigated. The first set of ionic liquids will be based on 1-alkyl-3-methylimidazolium cations with varying alkyl chain length paired with anions such as chloride and bistrifluoromethylsulfonylimide, which have been studied in great detail and are likely to be manufactured in large quantities. The second set of ionic liquids will be comprised of the cation tetrabutylphosphonium with similar anions. These ionic liquids and their variations are less toxic than imidazolium-based ionic liquids and currently being studied as potential CO2 capture solvents. The work is inspired by the fact that ionic liquids defined as pure salts that are liquid at ambient conditions ? have emerged as promising new solvents for a range of technological applications including gas separations, lubrication, batteries, and as therapeutic agents. An explosion in ionic liquid research within academia and industry coupled with increasing likelihood of adoption of ionic liquids by industry has resulted in an urgent need to understand the environmental impact of these materials in terms of their fate, transport, and toxicity towards organisms. A number of toxicity bioassay studies have suggested that alkyl chain length, anion type, and lipophilicity all play a role in ionic liquid toxicity. However, a fundamental molecular level understanding of how these factors contribute to toxicity and how they can be manipulated to achieve desired toxicity characteristics of ionic liquids is lacking. To address this critical gap in knowledge, the proposed linked molecular simulation, biophysical experimentation, and toxicity bioassay approach is highly promising as it will result in a greater mechanistic understanding of ionic liquid toxicity than would be possible by a single technique alone. Although the proposed research is targeted at two classes of ionic liquids, the fundamental understanding gained has broad implications and can be integrated into the rational design of less toxic ionic liquids which will lead to development of chemical processes and products with reduced environmental footprint. This work also benefits current efforts aimed at exploiting therapeutic properties of ionic liquids, where knowledge of ionic liquid interactions with the lipid bilayer is critical. The study will provide essential information on the characteristics of the cell membrane that determine susceptibility to disruption by ionic liquids, which may ultimately enable the engineering of microorganisms able to transport ionic liquids inside the cell for biodegradation of ionic liquids. Another major goal of this research is to teach and train students how to make an intellectual connection between molecular level interactions and the manifestation of such interactions at a systems level by working in an interdisciplinary experimental/computational environment. Efforts to recruit women and students from underrepresented groups will follow the PI?s proven methods and will build on several existing programs at Notre Dame. A wide dissemination of the results from this activity to a broader audience is planned through the Notre Dame Public Affairs Office