ELECTROSTATIC SELF-ASSEMBLY IN BIOLOGICAL SYSTEMS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们建议研究宏观离子在带电脂膜中诱导的孔形成。 静电相互作用对于分子“打孔器”是很重要的，例如 跨细胞膜的蛋白转导结构域与膜活性抗菌剂 穿透细胞膜的多肽。该程序集中于两个同源系统。 (1)人类免疫缺陷病毒tat蛋白转导结构域(Ptd)是一种高阳离子富含精氨酸的多肽。 可以在阴离子真核细胞膜上以异常高的 效率。我们的目标是探索富含精氨酸的细胞穿透肽，以及合成的 具有定义明确的精氨酸和其他氨基酸序列的类似物，以阐明 (2)抗菌肽(AMP)是多种多细胞生物天然免疫的重要组成部分。Theta-Defensins是一种具有高度选择性的抗菌肽。RTD-1和BTD-7 Theta-Defensins具有抗HIV和SIV活性。前列环素(PG-1)是另一种与theta-Defensins有70%序列同源性的抗菌肽。然而，前列环素对一些真核细胞也是有效的。我们的目标是了解氨基酸组成和位置上的微小差异如何导致多肽活性的巨大变化。像蛋白质转导结构域一样，这些阳离子多肽利用碱性氨基酸精氨酸，而不是赖氨酸和组氨酸。我们利用同步辐射X射线衍射仪研究了在这两种造孔剂存在下，脂泡的自组装结构、相互作用和相行为。这一研究计划的成功可以在广泛的生物技术应用方面带来进展，例如改进的药物输送系统和抗生素的设计规则。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We propose to investigate macro-ion induced pore formation in charged lipid membranes. Electrostatic interactions are known to be important for molecular "hole punchers" such as protein transduction domains that cross cell membranes, and membrane-active antimicrobial peptides that permeate cell membranes. The program concentrates on two cognate systems. (1) The HIV TAT protein transduction domain (PTD) is highly cationic arginine-rich peptide that can translocate across anionic eukaryotic cell membranes with anomalously high efficiency. We aim to explore arginine-rich, cell penetrating peptides, as well as synthetic analogs with well-defined sequences of arginines and other amino acids, in order to elucidate their mode of action on membranes.(2) Antimicrobial peptides (AMP) comprise a key component of innate immunity for a wide range of multicellular organisms. Theta-defensins are highly selective antimicrobial peptides. RTD-1 and BTD- 7 theta-defensins have activity against HIV and SIV. Protegrin (PG-1) is another antimicrobial peptide with 70% sequence homology to theta-defensins. However, protegrin is also active against some eukaryotic cells. We aim to understand how slight differences in amino acid composition and placement lead to large changes in peptide activity. Like protein transduction domains these cationic peptidesutilize the basic amino acid arginine over lysine and histidine. We investigate the self-assembled structure, interactions, and phase behavior of lipid vesicles in the presence of these two types of pore-forming agents using synchrotron x-ray diffraction. Success in this program of research can lead to advances across a broad range of biotechnological applications, such as improved drug delivery systems and design rules for antibiotics.