Computational Investigations of Compositional Heterogeneities in Lipid Membranes

技术摘要：该奖项支持生物膜纳米级非均质性研究的理论研究和教育，即所谓的“筏”。研究这些生物膜的横向异质性是出于了解其生理和结构功能的需要。广泛的研究表明，哺乳动物细胞以小区域的形式表现出成分的异质性，称为筏，直径范围在50到200纳米之间。脂筏被认为是高度动态的，富含鞘脂（主要是饱和脂）和胆固醇。脂筏也被认为在多种生理功能中发挥作用，包括蛋白质运输、脂质分选、信号转导和内吞作用。与合成膜相比，在研究活的生物系统时，提出了一些引人注目的问题。在合成脂质膜上的大量实验证明了结构域的存在，从而支持生物膜中的筏模型。然而，生物膜中的脂筏是纳米级的，比合成膜中的脂结构域小几个数量级。本研究通过系统和大尺度中尺度数值模拟研究了筏体的形成和膜非均质性的动力学。计算机模拟允许研究多组分膜的相行为，并研究导致生物膜中纳米级脂筏稳定性的可能机制。利用最近开发的模型的粗粒度分子动力学（CGMD）模拟，PI将研究由饱和脂质、不饱和脂质和胆固醇组成的三元脂质混合物的相行为，特别关注两相液-液共存，这与生物膜中的脂筏有关。一个基于软核相互作用的更粗粒度的自组装两亲体模型将被开发出来，并将用于研究两相液-液共存中的三组分脂膜。该模型将与将耗散粒子动力学（DPD）与半正则蒙特卡罗技术相结合的混合方法结合使用。除了基础研究之外，该奖项还具有教育意义，并可能在其他领域产生更广泛的影响。由于其多学科性质，该研究将对物理科学和生命科学产生广泛的影响。本研究涉及研究生和本科生。这个提议的研究的计算性质使它特别适合本科生。这项研究也将使孟菲斯大学新的计算物理专业受益。这项研究将与孟菲斯大学目前的教育议程相结合，孟菲斯大学有大量的少数民族学生。孟菲斯大学的高级本科生物物理学课程和研究生计算课程受益于这个项目，因为它靠近一个活跃的研究项目，可以将该领域的研究活动的特征联系起来。PI还与物理系的其他教员合作，创建了一个高中物理实习项目，每年将从孟菲斯地区的高中中挑选一些学生，让他们参与研究体验项目。摘要：该奖项支持生物膜中分子聚集研究的理论研究和教育，即所谓的“筏”。对生物膜中这些分子分组的研究是出于了解其生理和结构功能的需要。广泛的研究表明，所有动物细胞都形成这些小区域，称为筏，直径约为细胞大小的1/100。脂筏被认为是高度动态的，主要是饱和脂质和胆固醇。脂筏也被认为在多种生理功能中发挥作用，包括物质进出细胞的转移。与合成膜相比，在研究活的生物系统时，提出了一些引人注目的问题。在合成脂质膜上的大量实验证明了结构域的存在，从而支持生物膜中的筏模型。然而，生物膜中的脂筏比合成膜中的脂结构域小100倍。这只是本研究中所调查的木筏的一个方面。本研究通过系统和大规模的数值模拟研究了筏体的形成和膜组成的动力学。计算机模拟允许研究膜的组成和调查可能的机制导致脂筏的稳定性。除了基础研究之外，该奖项还具有教育意义，并可能在其他领域产生更广泛的影响。由于其多学科性质，该研究将对物理科学和生命科学产生广泛的影响。本研究涉及研究生和本科生。这个提议的研究的计算性质使它特别适合本科生。这项研究也将使孟菲斯大学新的计算物理专业受益。这项研究将与孟菲斯大学目前的教育议程相结合，孟菲斯大学有大量的少数民族学生。孟菲斯大学的高级本科生物物理学课程和研究生计算课程受益于这个项目，因为它靠近一个活跃的研究项目，可以将该领域的研究活动的特征联系起来。PI还与物理系的其他教员合作，创建了一个高中物理实习项目，每年将从孟菲斯地区的高中中挑选一些学生，让他们参与研究体验项目。

TECHNICAL ABSTRACT:This award supports theoretical research and education in the study of nanoscale heterogeneities in biological membranes, so called ''rafts''. Research on these lateral heterogeneities in biomembranes is motivated by a need to know their physiological and structural functions. The is extensive research indicating that mammalian cells exhibit compositional heterogeneities in the form of small domains, called rafts, with diameter ranging between 50 and 200 nm. Lipid rafts are believed to be highly dynamic, rich in sphingolipids, which are mainly saturated lipids, and cholesterol. Lipid rafts are also believed to play a role in a variety of physiological functions including protein trafficking, lipid sorting, signal transduction, and endocytosis. There are striking questions raised when studying living biological systems in comparison to synthetic membrane. Numerous experiments on synthetic lipid membranes, demonstrated the existence of domains, thus supporting the raft model in biomembranes. However, lipid rafts in biomembranes, which are nanoscale in size, are orders of magnitude smaller than the lipid domains in synthetic membranes. The present research investigates raft formation and dynamics of membrane heterogeneities through systematic and large scale mesoscale numerical simulations. Computer simulations allow the study of phase behavior of multicomponent membranes and investigate possible mechanisms leading to the stability of nanoscale lipid rafts in biomembranes. Using coarse-grained molecular dynamics (CGMD) simulations of a recently developed model, the PI will investigate the phase behavior of ternary lipid mixtures composed of a saturated lipid, an unsaturated lipid and cholesterol, with a particular focus on the two-phase liquid-liquid coexistence, which is relevant to the lipid rafts in biomembranes. A more coarse-grained model based on soft-core interactions will be developed for self assembled amphiphiles and will be used to investigate three-component lipid membranes in the two-phase liquid-liquid coexistence. The model will be used in conjunction with a hybrid approach combining dissipative particle dynamics (DPD) with semi-grand canonical Monte Carlo technique. Beyond the basic research, the award has educational implications and potential broader impact in other areas. Due to its multidisciplinary nature, the research will have a broad impact on both the physical and life sciences. Graduate and undergraduate students are involved in this research. The computational nature of this proposed research makes it particularly accessible to undergraduate students. This research will also benefit the new Computational Physics Concentration at the University of Memphis. The research will be integrated with the current educational agenda of the University of Memphis which has a significant minority student population. The senior undergraduate biophysics course and the graduate computational course at the University of Memphis benefit from this program by the proximity of an active research program which can relate the character of research activities in this area. The PI is also teaming up with other faculty members at the physics department to create a high school physics internship program in which a number of students will be selected every year from the Memphis area high schools and will be involved in research experience projects.NONTECHNICAL ABSTRACT:This award supports theoretical research and education in the study of molecular clustering in biological membranes, so called ''rafts''. Research on these molecular groupings in biomembranes is motivated by a need to know their physiological and structural functions. The is extensive research indicating that all animal cells form these small domains, called rafts, with small diameter of around 1/100th the size of the cell. Lipid rafts are believed to be highly dynamic and mainly saturated lipids, and cholesterol. Lipid rafts are also believed to play a role in a variety of physiological functions, including transfer of materials into and out of a cell. There are striking questions raised when studying living biological systems in comparison to synthetic membrane. Numerous experiments on synthetic lipid membranes, demonstrated the existence of domains, thus supporting the raft model in biomembranes. However, lipid rafts in biomembranes are a hundred times smaller than the lipid domains in synthetic membranes. This is only one aspect of rafts that is investigated in this research. The present research investigates raft formation and dynamics of membrane composition through systematic and large scale numerical simulations. Computer simulations allow the study of membrane composition and investigate possible mechanisms leading to the stability of lipid rafts. Beyond the basic research, the award has educational implications and potential broader impact in other areas. Due to its multidisciplinary nature, the research will have a broad impact on both the physical and life sciences. Graduate and undergraduate students are involved in this research. The computational nature of this proposed research makes it particularly accessible to undergraduate students. This research will also benefit the new Computational Physics Concentration at the University of Memphis. The research will be integrated with the current educational agenda of the University of Memphis which has a significant minority student population. The senior undergraduate biophysics course and the graduate computational course at the University of Memphis benefit from this program by the proximity of an active research program which can relate the character of research activities in this area. The PI is also teaming up with other faculty members at the physics department to create a high school physics internship program in which a number of students will be selected every year from the Memphis area high schools and will be involved in research experience projects.