SIMULATING MEMBRANE PERMEATION BY CATIONIC PEPTIDES

模拟阳离子肽的膜渗透

• 批准号: 8171906
• 负责人: Alemayehu A. Gorfe
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171906
• 关键词: Antibodies; Apoptosis; Arginine; Binding; Biological; Cell Proliferation; Cell membrane; Cells; Characteristics; Charge; Chemicals; Chemistry; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Electrostatics; Foundations; Free Energy; Funding; Future; Grant; Image; Immunotherapy; Inflammation; Institution; Islets of Langerhans Transplantation; Lipid Bilayers; Lipids; Lysine; Membrane; Membrane Potentials; Nucleic Acids; Oxidative Stress; Peptides; Perception; Property; Proteins; Regulation; Report (document); Research; Research Personnel; Resources; Role; Simulate; Solid; Solvents; Source; Staging; Thermodynamics; Traumatic Stress Disorders; United States National Institutes of Health; Vaccines; base; design; molecular dynamics; novel; programs; tumor; uptake; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The discovery of highly charged membrane penetrating peptides two decades ago has changed the perception that the plasma membrane is an impermeable barrier. This presented an important challenge for physical organic chemists: how does the interplay between electrostatics and vdW forces is modulated during uptake and permeation? Which structural and dynamical features of the cell penetrating peptides (CPPs), and of the lipid and solvent molecules, alter to allow a hydrophilic peptide to cross a hydrophobic core of membrane? Furthermore, numerous reports documented the capability of CPPs to transport hydrophilic cargo of varying sizes across membranes. CPPs are therefore being investigated for a variety of applications, including for the development of protein-based vaccines, the study of apoptosis and cell proliferation, transplantation of Islet cells, treatment of oxidative stress disorders, immunotherapy of tumors, and regulation of inflammation. Delivery of nucleic acids, antibodies, and imaging agents are some of the other applications of CPPs. It is apparent that physicochemical data on CPP-membrane interactions is vital for the design of novel and more effective vectors. However, in contrast to the accumulated biological and biophysical macroscopic data, information on the basic chemistry of CPP-membrane interactions is scarce. As a result, atomic-level understanding of how CPPs bind to and subsequently cross lipid bilayers is currently limited. In order to fill this void, we devised a research program that aims at characterizing the structural and thermodynamic principles underlying CPP uptake and membrane permeation. Our research will use first-principles computations, based around molecular dynamics simulations and free energy calculations, to unravel the roles of cationic charge content and amphiphiliciy of CPPs, and of membrane potential and counterions. The study will be carried out in three stages. In the first stage of the project period, we will probe which characteristics of CPPs are responsible for membrane uptake. To this end, we will compare the bilayer binding properties of arginine-rich, lysine-rich and amphipatic peptides. The second stage will focus on deciphering the mechanism of membrane translocation, with emphasis on the roles of membrane potential and counterions. The last stage concerns cargo delivery. The results will establish the physical and chemical principles of membrane uptake and permeation of CPPs by delineating the structural and energetic determinants of CPP-membrane interactions, thus laying a solid foundation for future applications-oriented studies.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 二十年前发现高电荷膜穿透肽的发现改变了人们对质膜是不可渗透的屏障的看法。这给物理有机化学家带来了重要的挑战：在吸收和渗透期间，静电和VDW力之间的相互作用如何调节？细胞穿透性肽（CPP）以及脂质和溶剂分子的哪些结构和动力学特征改变以允许亲水肽跨越膜的疏水核心？此外，许多报告记录了CPP在整个膜中运输各种尺寸的亲水性货物的能力。因此，正在研究各种应用中CPP，包括开发基于蛋白质的疫苗，凋亡和细胞增殖的研究，胰岛细胞的移植，氧化应激障碍的治疗，肿瘤的免疫疗法以及炎症调节。核酸，抗体和成像剂的递送是CPP的其他某些应用。显然，有关CPP膜相互作用的物理化学数据对于新颖和更有效的向量的设计至关重要。但是，与累积的生物学和生物物理宏观数据相反，有关CPP膜相互作用的基本化学的信息很少。结果，目前对CPP与CPP结合和随后的交叉脂质双层的理解是有限的。为了填补这一空白，我们设计了一个研究计划，旨在表征CPP摄入和膜渗透的结构和热力学原理。我们的研究将使用基于分子动力学模拟和自由能计算的第一原理计算来揭示CPPS的阳离子电荷含量和两亲性的作用，以及膜电位和反面的作用。该研究将在三个阶段进行。在项目时期的第一阶段，我们将探测CPP的哪些特征负责膜吸收。为此，我们将比较富含精氨酸，富含赖氨酸和两亲的肽的双层结合特性。第二阶段将着重于解密膜易位的机理，重点是膜电位和柜台的作用。最后阶段涉及货物交付。结果将通过描述CPP膜相互作用的结构和能量决定因素来确定膜摄取和CPP渗透的物理和化学原理，从而为未来的面向应用的研究奠定了坚实的基础。