Spontaneous Membrane Translocating Peptides

自发膜转位肽

• 批准号: 9536104
• 负责人: WILLIAM C WIMLEY
• 金额: $ 31.62万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9536104
• 关键词: Arginine; Behavior; Binding; Biological; Biological Assay; Bypass; Cations; Cells; Charge; Chemicals; Communities; Drug Design; Electrostatics; Engineering; Ensure; Family; Future; Goals; Hydrocarbons; Hydrophobicity; Learning; Leucine; Lipid Bilayers; Lipids; Luciferases; Measurement; Measures; Membrane; Modification; Molecular Chaperones; Movement; Neutron Diffraction; Oligonucleotides; Peptide Nucleic Acids; Peptides; Population; Property; RNA Splicing; Role; Small Interfering RNA; Solubility; Structure; Structure-Activity Relationship; System; Testing; Variant; Vesicle; Work; X ray diffraction analysis; analog; base; biophysical properties; design; inorganic phosphate; knock-down; novel; penetratin; physical property; protein expression; response; solute; synthetic nucleic acid

Summary The hydrocarbon core of a bilayer is normally a strict barrier to the passage of polar or charged solutes. We have discovered a novel class of cationic peptides that efficiently cross this barrier without causing bilayer permeabilization. These peptides are fundamentally different from other classes of membrane active peptides, and may hold the key to understanding how to bypass the barrier of the hydrocarbon core on demand. Yet, the determinants of this behavior are currently unknown. Here we will explore the physical chemical basis of peptide translocation by comprehensively examining rationally designed sequence variants of a known translocating peptide. The overarching hypothesis of this proposal is that translocation occurs only if the peptides have a specific translocation-enabling sequence motif and optimal hydrophobicity. Here we will test the hypothesis that translocation of peptides across bilayers requires optimal hydrophobicity that ensures a low steady state population in a membrane, and a specific sequence motif consisting of two arginines spaced by two hydrophobic residues, embedded in a hydrophobic sequence. We will determine the importance of these translocation-permissive properties by varying them independently by rational sequence modification and assessing the effect on (1) translocation across bilayers, (2) binding to bilayers, and (3) the structural response of the bilayer to the peptides.

概括 双层的碳氢化合物核心通常是极性或带电分子通过的严格屏障。 溶质。我们发现了一类新型阳离子肽，可以有效穿过这一屏障 而不引起双层通透。这些肽与其他肽有根本的不同 膜活性肽的类别，并且可能是了解如何绕过的关键 碳氢化合物核心的屏障按需。然而，这种行为的决定因素是 目前未知。在这里，我们将探讨肽易位的物理化学基础 全面检查已知易位的合理设计的序列变体 肽。该提案的总体假设是，只有当 肽具有特定的易位序列基序和最佳的疏水性。 在这里，我们将测试肽跨双层的易位需要最优的假设 疏水性确保膜中的低稳态群体，以及特定的 由两个疏水残基间隔的两个精氨酸组成的序列基序，嵌入 疏水序列。我们将确定这些易位许可的重要性 通过合理的序列修饰独立地改变它们并评估它们的特性 对 (1) 跨双层易位、(2) 与双层结合以及 (3) 结构响应的影响 双层到肽。