Simulation studies of permeability and melting behavior in gel-phase lipid bilayers

凝胶相脂质双层渗透性和熔化行为的模拟研究

• 批准号: 1213904
• 负责人: James Kindt
• 金额: $ 40.3万
• 依托单位: Emory University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1213904&HistoricalAwards=false
• 关键词: Simulation; studies; permeability; melting; behavior

James T. Kindt at Emory University is supported by the Chemical Theory, Models and Computational Methods program in lipid bilayer research. The dramatically different properties of lipid bilayers in the ordered gel phase and the disordered fluid phase (found below and above the transition temperature, respectively) have found applications in thermoresponsive liposome technology. The proposed research activities in the Kindt group will use atomistic molecular dynamics and mixed Monte Carlo/molecular dynamics (MCMD) methods to explore aspects of gel phase structure, dynamics, and thermodynamics relevant to these properties. First, the behaviors of several force-fields will be evaluated for their agreement with x-ray scattering data and experimental gel/fluid transition temperatures. Secondly, hypotheses for origins of the experimentally determined peak in bilayer permeability near the transition temperature will be explored. Comparison of the free energy of ion and small molecule passage through fluid, gel, and interfacial zones of a bilayer at coexistence will be used to test the "leaky interface" explanation, and continuum-based modeling of surface stress relaxation will be used to test the "surface compressibility" explanation. Thirdly, using MCMD, partitioning of lipid "dopants" within the interior and interfaces of gel phase domains will be evaluated. Finally, the dynamics of gel-phase vesicle response to ultrafast temperature jumps will be modeled, in close conjunction with experimental collaborators, using atomistic simulation for sub-microsecond dynamics, coarse-grained simulation for longer-time relaxation, and phenomenological kinetic modeling.Lipid molecules tend to arrange themselves in water into double-layer sheets called bilayers. Living organisms use lipid bilayers to form boundaries between and within cells. Lipids can also be manufactured into nanoscopic capsules (called liposomes or vesicles) to contain a variety of substances, which find uses in biotechnology, drug delivery, cosmetics and personal care products, agriculture and food science. These are useful if the capsules are designed to empty their contents in response to some "switch". Some lipid bilayers have a built-in "switch" in the form of an inherent sensitivity to temperature: changing the temperature from just below to just above a specific "transition temperature" will cause the liposome to undergo a change in state, similar to melting. The transition influences the shape and permeability of liposomes -- below the transition temperature, the liposome will release contents very slowly, while above the transition temperature, molecules can escape more rapidly. For reasons that are not fully understood, the permeability is strongly enhanced at temperatures very near the transition temperature. Research in the Kindt group will use computer models of molecular behavior to investigate the structure of bilayers and liposomes near the transition temperature, where the lipid structure is partially melted and partially solid, to test hypotheses about this enhancement. In conjunction with colleagues who are measuring the rate of vesicle melting in the laboratory, we will also use our simulations to help describe the structure of the lower-temperature phase of the vesicle, which is not uniform and spherical but has facets and ridges, and the factors that determine the rate of the melting transition. The goal is to discover fundamental reasons for observed liposome behaviors, so that these technologies can be approved and applied more broadly. As a secondary product of this research, the Kindt group will produce molecular animations of our simulations to educate students and the public about lipid behavior over the World Wide Web.

埃默里大学的 James T. Kindt 得到了脂双层研究化学理论、模型和计算方法项目的支持。有序凝胶相和无序流体相（分别低于和高于转变温度）中脂质双层的显着不同特性已在热响应脂质体技术中得到应用。 Kindt 小组拟议的研究活动将使用原子分子动力学和混合蒙特卡罗/分子动力学 (MCMD) 方法来探索与这些特性相关的凝胶相结构、动力学和热力学方面。 首先，将评估几个力场的行为与 X 射线散射数据和实验凝胶/流体转变温度的一致性。其次，将探讨实验确定的接近转变温度的双层渗透性峰值的起源假设。比较共存时离子和小分子通过流体、凝胶和双层界面区域的自由能将用于检验“泄漏界面”的解释，并且基于连续介质的表面应力松弛模型将用于检验“表面压缩性”的解释。 第三，使用MCMD，将评估脂质“掺杂剂”在凝胶相域的内部和界面内的分配。 最后，将与实验合作者密切合作，使用亚微秒动力学的原子模拟、较长时间弛豫的粗粒度模拟以及唯象动力学建模，对凝胶相囊泡对超快温度跳跃响应的动力学进行建模。脂质分子倾向于将自己在水中排列成称为双层的双层片。 活生物体使用脂质双层在细胞之间和细胞内形成边界。脂质还可以被制造成纳米胶囊（称为脂质体或囊泡）来容纳各种物质，这些物质可用于生物技术、药物输送、化妆品和个人护理产品、农业和食品科学。 如果胶囊被设计为响应某些“开关”而清空其内容物，则这些是有用的。 一些脂质双层具有对温度固有敏感性形式的内置“开关”：将温度从略低于特定“转变温度”改变到略高于特定“转变温度”将导致脂质体发生状态变化，类似于熔化。这种转变影响脂质体的形状和渗透性——低于转变温度，脂质体将非常缓慢地释放内容物，而高于转变温度，分子可以更快地逸出。 由于尚未完全了解的原因，在非常接近转变温度的温度下，渗透性会大大增强。 Kindt 小组的研究将使用分子行为的计算机模型来研究接近转变温度的双层和脂质体的结构，其中脂质结构部分熔化，部分固态，以测试有关这种增强的假设。 与在实验室测量囊泡熔化速率的同事一起，我们还将利用我们的模拟来帮助描述囊泡低温相的结构（它不是均匀的球形，而是具有小面和脊），以及决定熔化转变速率的因素。 目标是发现观察到的脂质体行为的根本原因，以便这些技术能够得到更广泛的批准和应用。 作为这项研究的第二个产品，Kindt 小组将制作我们模拟的分子动画，以教育学生和公众了解万维网上的脂质行为。