Computational Studies of Biological Membranes

生物膜的计算研究

• 批准号: 9631050
• 负责人: Eric Jakobsson
• 金额: $ 27万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9631050&HistoricalAwards=false
• 关键词: Computational; Studies; Biological; Membranes

9631050 Jakobsson The general objectives of the proposed work are to improve our understanding of the physical principles underlying the structure and functional mechanisms of biological membranes. The methodologies employed are computer simulations and statistical mechanical theory. The overall strategy of our laboratory is to validate computational methods on relatively simple systems that are well characterized by experimental measurement. Then we can extend the methods to using them to explore more complex systems of biological interest. In ion channels, the simplest and best characterized channel is the antibiotic channel-former gramicidin. In membranes themselves, the simplest system is a homogenous lipid bilayer. Our initial approach then has been to use gramicidin channels and pure homogenous lipid bilayers as test systems to develop efficient and accurate methodologies for the simulation of membrane proteins and membranes themselves. We have now begun to use these methodologies to understand more complex systems of interest. These more complex systems include the gramicidin channel-lipid complex, biologically important specific ion channels, such as voltage-gated sodium and potassium channels, and membranes interacting with signal peptides and organic molecules. An ultimate goal is to understand the complete interactions of large proteins with membranes and to understand the structure of heterogenous membranes, that include proteins, different species of lipids, and other molecules such as cholesterol. But the necessary intermediate goal, which we are pursuing in the next phase of our laboratory's work, is to understand the details of the interactions of different types of molecules in the membrane environment. These details will provide the building blocks for the more comprehensive understanding that it our ultimate goal. %%% Membranes are the surfaces of the cells that make up the building blocks of all living things. The forces that cause biological membranes to fo rm are much like the forces that cause the formation of soap bubbles, but membranes are much more chemically complicated than soap bubbles. In fact, many physicists believe that biological membranes are the most complicated condensed matter (liquid or solid) in the known universe. The basic building blocks of biological membranes are fatty molecules called phospholipids. In addition to phospholipids, biological membranes have many proteins embedded in them that carry out important biological functions. These functions include transporting materials between the inside of the cell and the outside, and sending and receiving chemical signals from other cells. For many complicated systems, computer simulations can help in understanding how the systems work. This is because the computer can show details that are very hard to measure directly. The current project is to use computer simulations to see the details of how membranes form, and how they function. In the computer simulations, we can see details of the interactions between the membrane phospholipid molecules and the surrounding water, details of the interactions between phospholipid molecules and proteins in the membrane, and details of the protein function. This project looks especially at one type of membrane protein called an ion channel. Ion channels are proteins whose function is to move across the membrane charged atoms called ions. One of the ion channels studied in this project is gramicidin, an antibiotic which kills cells of other organisms when it is inserted in their membranes, by making them too leaky to ions. Other ion channels studied in this project are important in generating electrical signals in cells. The goal of the project is to contribute to a basic understanding of biological membrane function. This is important both because of the inherent fascination of this extremely complicated type of matter and also because of the importance of understanding how biological function comes from the behavior of individua l molecules. ***

9631050 Jakobsson所提出的工作的一般目标是提高我们对生物膜结构和功能机理基础的物理原理的理解。 所采用的方法是计算机模拟和统计机械理论。 我们实验室的总体策略是验证以实验测量为特征的相对简单系统的计算方法。 然后，我们可以扩展方法来使用它们来探索更复杂的生物学兴趣系统。 在离子通道中，最简单，最佳的通道是抗生素通道形成剂格拉米霉素。 在膜本身中，最简单的系统是同质脂质双层。 然后，我们的最初方法是使用谷霉素通道和纯均匀的脂质双层作为测试系统，以开发有效，准确的方法来模拟膜蛋白和膜本身。 现在，我们已经开始使用这些方法来了解更复杂的感兴趣系统。 这些更复杂的系统包括Gramicidin通道脂质复合物，生物学上重要的特定离子通道，例如电压门控钠和钾通道，以及与信号肽和有机分子相互作用的膜。 最终目标是了解大蛋白与膜的完整相互作用，并了解包括蛋白质，不同种类的脂质物种以及其他分子（例如胆固醇）的异质膜结构。 但是，我们在实验室工作的下一阶段所追求的必要的中间目标是了解膜环境中不同类型分子的相互作用的细节。 这些详细信息将为我们的最终目标提供更全面的理解。 %% %%膜是构成所有生物构建基块的细胞的表面。 引起生物膜的力的力很像引起肥皂泡形成的力，但是膜比肥皂泡更复杂。 实际上，许多物理学家认为生物膜是已知宇宙中最复杂的凝结物（液体或固体）。 生物膜的基本构件是称为磷脂的脂肪分子。 除磷脂外，生物膜中还嵌入了许多蛋白质，它们具有重要的生物学功能。 这些功能包括在细胞内部和外部之间运输材料，以及从其他细胞发送和接收化学信号。 对于许多复杂的系统，计算机模拟可以帮助了解系统的工作方式。 这是因为计算机可以显示很难直接测量的详细信息。 当前的项目是使用计算机模拟来查看膜形成方式及其功能的详细信息。 在计算机模拟中，我们可以看到膜磷脂分子与周围水之间的相互作用的细节，膜中磷脂分子和蛋白质之间相互作用的细节以及蛋白质功能的细节。 该项目尤其关注一种称为离子通道的膜蛋白。 离子通道是蛋白质的功能，其功能是在称为离子的膜充电原子上移动。 该项目中研究的一个离子通道之一是Gramicidin，一种抗生素，当将其插入其膜中时，可以杀死其他生物体的细胞，从而使它们对离子漏水。 该项目中研究的其他离子通道对于在细胞中产生电信号很重要。该项目的目的是为生物膜功能的基本理解做出贡献。 这既重要，这既是因为这种非常复杂的物质的固有迷恋，又是因为了解生物学如何来自个体分子的行为的重要性。 ***