Mechanism of membrane pore formation by antimicrobial peptides

抗菌肽膜孔形成机制

• 批准号: 9197316
• 负责人: THEMIS LAZARIDIS
• 金额: $ 30.14万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197316
• 关键词: Alamethicin; Anti-Bacterial Agents; Antibiotics; Behavior; Benchmarking; Binding; Biohazardous Substance; Biological; Biology; Budgets; Collaborations; Consensus; Data; Dimerization; Dyes; Electrophysiology (science); Elements; Environment; Extravasation; Fluorescence; Fluorescence Resonance Energy Transfer; Free Energy; Geometry; Growth; Human; Infection; Ions; Kansas; Kinetics; Letters; Lipid Bilayers; Lipids; Mammalian Cell; Measurement; Membrane; Methodology; Methods; Modeling; Molecular; Organism; Peptides; Process; Property; Radial; Resistance; Resource Sharing; Scheme; Shapes; Solvents; Structure; Surface; Testing; Thermodynamics; Toxic effect; Universities; Vertebrates; Work; analog; antimicrobial; antimicrobial peptide; base; computer studies; computing resources; design; dimer; experimental study; human subject; human subject protection; improved; insight; magainin; membrane model; microbial; molecular dynamics; novel; peptide structure; peptidomimetics; protegrins; protein aminoacid sequence; simulation; success; synergism; theories

Antimicrobial peptides provide natural defense against microbial infection and thus hold promise as the basis of new antibiotics. Substantial evidence suggests that they target the bacterial membranes, by either forming pores or disintegrating them. However, an understanding of this process to the level of predicting the behavior of specific peptides is lacking. Over the last few years the PI’s group used novel implicit membrane modeling, as well as detailed all-atom simulations, to obtain significant insights into the function of these peptides. The PI now aims to use a multipronged approach that encompasses all-atom simulations, implicit-solvent simulations, and molecular thermodynamic modeling, to develop a systematic approach that predicts the structure of peptide-stabilized membrane pores. Close interaction with experimental labs will help validate the predicted models. This work has three aims. The first focuses on the β-hairpin antimicrobial peptide protegrin, and aims to elucidate whether it forms complete β-barrels, incomplete barrels (arcs), or classical toroidal pores. Electrophysiology, dye leakage, and antimicrobial activity measurements will be used to validate the theoretical results. The other two aims provide key elements in a comprehensive theory of peptide-induced membrane pore formation: peptide-peptide interactions and the free energy of membrane deformation. The extent of interactions between peptides in the process of pore formation is a crucial unsolved problem. The PI’s group will first validate the implicit solvation models by comparison to experiments and explicit simulation potentials of mean force and then proceed to characterize the extent of aggregation of melittin and magainin on membrane surfaces and in pores. Mixtures of magainin with PGLa will also be considered to address the observed synergy between these two peptides. The third aim is to include in the theory the free energy of membrane deformation. The free energy of a peptide-stabilized pore contains contributions from peptide-pore interactions, peptide-peptide interactions and membrane deformation. Pore structure is characterized by four properties: size, shape, headgroup distribution, and charge distribution in mixed membranes. All-atom simulations will be used to obtain data that will parameterize an analytical function of these four properties. This function, together with implicit-solvent simulations, will be used to determine profiles of free energy as a function of radius and lowest free energy peptide-pore structures. The resulting structures will be tested by all-atom simulations. The pore structure of different peptides in neutral and charged membranes should provide a definitive answer to the origin of the difference in selectivity between melittin and magainin and a firm basis for the design of peptides or peptidomimetics with high potency and low toxicity.

抗菌胡椒提供了针对微生物感染的自然防御，因此保持了前景 新的抗生素。大量证据表明，它们通过形成，靶向细菌膜 毛孔或分解它们。但是，对这一过程的理解达到了预测行为的水平 缺乏特定的宠物。在过去的几年中 以及详细的全原子模拟，以获得对这些肽功能的重要见解。 pi 现在，旨在使用包含全原子模拟，隐式溶剂模拟的多收益方法， 和分子热力学建模，以开发一种系统的方法来预测 肽稳定的膜孔。与实验实验室的密切相互作用将有助于验证预测 型号。这项工作有三个目标。第一个侧重于β-发品抗菌肽肽蛋白，目标 阐明它是形成完整的β桶，不完全枪管（ARC）还是经典的环形孔。 电生理学，染料泄漏和抗菌活性测量将用于验证理论 结果。其他两个目标在肽诱导的膜的综合理论中提供了关键要素 孔格式：肽肽相互作用和膜变形的自由能。程度 在孔形成过程中，宠物之间的相互作用是一个关键的未解决问题。 Pi的小组 将首先与实验和显式模拟势相比，首先验证隐式解决方案模型 平均力，然后继续表征蜂素聚集的程度，并始终在膜上 表面和毛孔。 Everin与PGLA的混合物也将被视为解决观察到的 这两个宠物之间的协同作用。第三个目的是在理论中包括膜的自由能 形变。肽化孔的自由能包含肽孔相互作用的贡献， 肽肽相互作用和膜变形。孔结构的特征是四个特性： 混合膜中的大小，形状，头组分布和电荷分布。全原子模拟将是 用于获取将参数化这四个属性的分析函数的数据。此功能，一起 使用隐式溶剂模拟，将用于确定自由能的曲线作为半径和 最低的自由能肽孔结构。所得结构将通过全原子模拟进行测试。这 中性和充电膜中不同petides的孔结构应为 蜂素与始终之间选择性差异的起源，以及设计的坚定基础 具有较高效力和低毒性的肽或薄炎。