Modeling Membrane Binding and Permeabilization by Antimicrobial Peptides

抗菌肽的膜结合和透化建模

• 批准号: 8039981
• 负责人: THEMIS LAZARIDIS
• 金额: $ 25.88万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 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/8039981
• 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

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.

说明(申请人提供)：抗菌肽(AMPs)是一种小的，通常是阳离子的两亲性多肽，通过渗透病原体的膜为所有物种提供第一宿主防御机制。它们的正电荷被认为使它们对带负电荷的细菌膜比哺乳动物膜的中性外叶具有更高的亲和力。然而，它们的作用机制和活性的结构性决定因素仍然不清楚。在过去的两年里，我们的实验室开发了独特的建模工具，该工具隐含地考虑了膜环境，包括阴离子脂类和离子强度的影响，允许存在水孔，并纳入了跨膜电压的影响。我们建议应用这些方法来深入了解AMP的作用机制。其具体目标是：1.表征AMPs的膜吸附，寻找与活性和选择性的关系，即确定大量AMPs的膜结合构型和膜结合能作为膜电荷和离子强度的函数，并将其与观察到的多肽的实验性质，如抗菌光谱相关联。这些研究将检验静电学是靶标选择性的主要决定因素的假设。2.探讨AMPS的膜通透性机制。我们将建立桶形孔道、环状孔道和跨膜贝塔孔道的模型，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全两亲性使它们与环状膜孔结合得比平坦的膜表面更强。3.模型验证和改进后的AMPS的合理设计。序列修改将被建议用于毒性较小、更有效、在较低浓度和较高离子强度下更具活性的多肽。与领先的实验小组的合作将使我们能够对我们的设计进行实际测试。意义：了解AMPS的作用机制可能会导致新抗生素的发现。 公共卫生相关性：该项目旨在了解抗菌肽的作用机制，抗菌肽是一种通过渗透病原生物膜为所有物种提供第一宿主防御机制的小肽。这将通过计算研究它们与膜和膜孔的结合来实现。这些结果将被用来合理地设计这些多肽的改进版本，这些多肽可以用作新的抗生素。