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

James T.埃默里大学的Kindt得到了脂质双层研究中的化学理论，模型和计算方法计划的支持。在有序凝胶相和无序流体相（分别在转变温度以下和以上发现）中脂质双层的显著不同的性质已经在温敏脂质体技术中找到了应用。 Kindt小组的拟议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，将探讨在转变温度附近的双层渗透率的实验确定的峰值的起源的假设。离子和小分子通过流体，凝胶和双层的界面区共存的自由能的比较将被用来测试“泄漏界面”的解释，和基于连续介质的表面应力松弛的建模将被用来测试“表面可压缩性”的解释。 第三，使用MCMD，将评估凝胶相域的内部和界面内的脂质“掺杂剂”的分配。 最后，凝胶相囊泡对超快温度跳跃的响应动力学将与实验合作者密切合作，使用亚微秒动力学的原子模拟，长时间弛豫的粗粒度模拟和唯象动力学建模。脂质分子倾向于在水中排列成称为双层的双层片。 生物体使用脂质双层在细胞之间和细胞内形成边界。脂质也可以制成纳米级胶囊（称为脂质体或囊泡），以容纳各种物质，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。 如果胶囊被设计成响应于某种“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的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”将导致脂质体经历类似于熔化的状态变化。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，分子可以更迅速地逃逸。 由于尚未完全理解的原因，渗透性在非常接近转变温度的温度下强烈增强。 Kindt小组的研究将使用分子行为的计算机模型来研究在转变温度附近的双层和脂质体的结构，其中脂质结构部分熔化，部分固体，以测试有关这种增强的假设。 与在实验室中测量囊泡融化速率的同事一起，我们还将使用我们的模拟来帮助描述囊泡的低温相的结构，该结构不是均匀的和球形的，但具有小平面和脊，以及决定融化转变速率的因素。 其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，以教育学生和公众关于万维网上的脂质行为。

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.