Computational Analysis of Peptide/lipid Interactions and Organization at Membrane Surfaces

膜表面肽/脂质相互作用和组织的计算分析

• 批准号: 0212362
• 负责人: Diana Murray
• 金额: $ 38.83万
• 依托单位: Joan and Sanford I. Weill Medical College of Cornell University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0212362&HistoricalAwards=false
• 关键词: Computational; Analysis; Peptide; lipid; Interactions

The focus of this project is the development of numerical procedures for calculating the physical basis of the association of peptides with the membrane interface, the electrostatic forces involved in lateral redistribution of lipids, and detailed electrostatic properties of membrane systems based on more realistic models than have been used in the past. This project is based on two main hypotheses: 1) Physical forces-electrostatics and hydrophobicity-mediate the membrane association of amphipathic peptides: the electrostatic interactions occur between basic residues and acidic phospholipids, and the hydrophobic interactions are mediated via aromatic residues which partition into the polar headgroup region of the membrane. 2) Nonspecific electrostatic interactions provide the driving force for the observed lateral sequestration of multivalent acidic phospholipids by clusters of basic residues on membrane-adsorbed peptides corresponding to these basic domains. The finite difference Poisson-Boltzmann (FDPB) method, which is based on a continuum description of the aqueous solvent and a more detailed, atomic-level description of the macromolecules, has been remarkably successful in its ability to reproduce experimental measurements of the binding free energies of simple basic peptides that do not penetrate the membrane interface. Here, the continuum approach will be extended to peptides containing basic and aromatic residues that do penetrate the membrane interface. In addition, more realistic structural and theoretical models of peptide/membrane systems will be developed by incorporating snapshots from molecular dynamics simulations of membranes into FDPB calculations. Comparison with experiments at all levels will allow refinement of the theoretical methodology and provide valuable input to the experimental studies. The research described here is based on computational approaches and aims ultimately to provide a detailed theoretical description of the interactions between peripheral proteins and membranes. This research is important both because of the significance of the general area of peptide/membrane interactions and because many of the questions posed can only be approached with computational methods. This project involves the combined development and application of biophysical tools to describe problems that have not previously been studied with computational techniques and close collaborative interactions between computational and experimental work. The principal investigator is involved in a number of graduate programs such as the Program for Chemical Biology, the Biochemistry and Structural Biology Graduate Program, and the Keck Program in Cellular and Molecular Biophysics of Signal Transduction. The computational and research infrastructure being developed through projects such as this one is contributing to the enrichment of the graduate training environment.

该项目的重点是开发的数值计算程序的物理基础上的协会的肽与膜界面，参与横向重新分配的脂质的静电力，和详细的静电性能的膜系统的基础上更现实的模型比已经在过去使用。本课题基于两个主要假设：1）两亲性肽的膜结合是由静电力和疏水力介导的：静电作用发生在碱性残基和酸性磷脂之间，疏水作用则是通过芳香族残基介导的，芳香族残基分布在膜的极性头基区域。2)非特异性静电相互作用提供的驱动力，所观察到的多价酸性磷脂的横向隔离的碱性残基簇膜吸附的肽对应于这些基本域。有限差分泊松-玻尔兹曼（FDPB）方法，这是基于连续描述的水溶剂和更详细的，原子级的描述的大分子，已显着成功的能力，重现实验测量的结合自由能的简单的基本肽，不穿透膜界面。在这里，连续体方法将扩展到含有碱性和芳香族残基的肽，这些残基穿透膜界面。此外，更现实的肽/膜系统的结构和理论模型将开发纳入FDPB计算的分子动力学模拟的膜快照。与各级实验的比较将使理论方法得到完善，并为实验研究提供有价值的投入。这里描述的研究是基于计算的方法，最终目的是提供一个详细的外周蛋白质和膜之间的相互作用的理论描述。这项研究是重要的，因为肽/膜相互作用的一般领域的意义，因为许多问题只能用计算方法来处理。该项目涉及生物物理工具的综合开发和应用，以描述以前没有用计算技术研究过的问题，以及计算和实验工作之间的密切合作。主要研究者参与了许多研究生课程，如化学生物学课程，生物化学和结构生物学研究生课程，以及信号转导细胞和分子生物物理学的凯克课程。通过诸如此类的项目开发的计算和研究基础设施有助于丰富研究生培训环境。