Modeling Membrane Binding and Permeabilization by Antimicrobial Peptides

抗菌肽的膜结合和透化建模

基本信息

批准号：
8241062
负责人：
THEMIS LAZARIDIS
金额：
$ 26.15万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241062
关键词：
Accounting Adsorption Affect Affinity Agreement Alamethicin Anti-Bacterial Agents Antibiotics Antifungal Agents Attention Behavior Binding Biomedical Research Charge Climate Collaborations Comparative Study Data Defensins Detergents Development Elasticity Electrostatics Environment Free Energy Funding Goals Grant Host Defense Mechanism Human Infection Institutes Ionic Strengths Israel Lead Lipids Membrane Membrane Proteins Methods Microbial Antibiotic Resistance Modeling Modification Molecular Conformation Neutrons Organism Peptides Pharmaceutical Preparations Positioning Attribute Productivity Property Relative (related person)Sodium Chloride Structure Surface Testing United States National Institutes of Health Water antimicrobial antimicrobial peptide aqueous base beta barrel computer studies cost design expiration human neutrophil peptide 3 improved insight magainin medical schools membrane model microbial molecular dynamics novel protegrins public health relevance research study theories tool voltage

项目摘要

DESCRIPTION (provided by applicant): Antimicrobial peptides (AMPs) are small, usually cationic, amphipathic peptides that provide a first host defense mechanism for species in all kingdoms by permeabilizing the membrane of pathogenic organisms. Their positive charge is thought to afford them higher affinity for the negatively charged bacterial membranes relative to the neutral outer leaflet of mammalian membranes. However, their mechanism of action and structural determinants of activity are still unclear. Over the last two years our lab developed unique modeling tools that take into account the membrane environment implicitly, include the effect of anionic lipids and ionic strength, allow for the presence of an aqueous pore, and incorporate the effect of transmembrane voltage. We propose to apply these methods to gain insights into the mechanism of action of AMPs. The specific aims are: 1. Characterize membrane adsorption of AMPs and seek correlations with activity and selectivity, i.e. determine the membrane bound configuration and membrane binding energy of a large number of AMPs as a function of membrane charge and ionic strength and correlate these to the observed experimental properties of the peptides, such as antimicrobial spectrum. These studies will test the hypothesis that electrostatics is a major determinant of target selectivity. 2. Investigate mechanisms of membrane permeabilization by AMPs. We will build models of barrel-stave pores, toroidal pores, and transmembrane beta barrels and compare the free energy of their formation. We make the novel hypothesis that the imperfect amphipathicity of many antimicrobial peptides makes them bind toroidal membrane pores more strongly than flat membrane surfaces. 3. Testing of the models and rational design of improved AMPs. Sequence modifications will be proposed towards peptides that are less toxic, more potent, and more active at lower concentrations and higher ionic strength. Collaborations with leading experimental groups will allow us to put our designs to a practical test. Significance: Understanding the mechanism of action of AMPs could lead to the discovery of new antibiotics. Public Health Relevance: This project aims to understand the mechanism of action of antimicrobial peptides, small peptides that provide a first host defense mechanism for species in all kingdoms by permeabilizing the membrane of pathogenic organisms. This will be accomplished by computational studies of their binding to membranes and membrane pores. The results will be used to rationally design improved versions of these peptides that could be used as novel antibiotics.

描述（由申请人提供）：抗菌肽（AMP）是小的、通常是阳离子的两亲性肽，通过透化病原生物体的膜，为所有界中的物种提供第一宿主防御机制。相对于哺乳动物膜的中性外层，它们的正电荷被认为使它们对带负电的细菌膜具有更高的亲和力。然而，它们的作用机制和活性的结构决定因素仍不清楚。在过去的两年里，我们的实验室开发了独特的建模工具，隐含地考虑了膜环境，包括阴离子脂质和离子强度的影响，允许水孔的存在，并纳入跨膜电压的影响。我们建议应用这些方法来深入了解 AMP 的作用机制。具体目标是： 1. 表征 AMP 的膜吸附并寻求与活性和选择性的相关性，即确定大量 AMP 的膜结合构型和膜结合能作为膜电荷和离子强度的函数，并将它们与观察肽的实验特性，例如抗菌谱。这些研究将检验静电是目标选择性的主要决定因素的假设。 2. 研究 AMP 的膜透化机制。我们将建立桶板孔、环形孔和跨膜β桶的模型，并比较它们形成的自由能。我们提出了一个新的假设，即许多抗菌肽的不完美的两亲性使得它们与环形膜孔的结合比平坦膜表面的结合更牢固。 3.模型测试和改进AMP的合理设计。将建议对肽进行序列修饰，使其在较低浓度和较高离子强度下毒性更小、更有效、更活跃。与领先的实验小组的合作将使我们能够将我们的设计进行实际测试。意义：了解 AMP 的作用机制可能有助于发现新的抗生素。公共卫生相关性：该项目旨在了解抗菌肽的作用机制，这种小肽通过透化病原生物的膜为所有物种提供第一个宿主防御机制。这将通过它们与膜和膜孔的结合的计算研究来完成。研究结果将用于合理设计这些肽的改进版本，可用作新型抗生素。