Collaborative Research: Lipid Bilayers and Membrane Active Peptides

合作研究：脂质双层和膜活性肽

• 批准号: 1709792
• 负责人: Gavin King
• 金额: $ 24万
• 依托单位: University of Missouri-Columbia
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1709792&HistoricalAwards=false
• 关键词: Collaborative; Research; Lipid; Bilayers; Membrane

Non-Technical:The work under this award will reveal the fundamental principles of sequence and structure for pH-triggered and pH-insensitive peptides that cause macromolecule-sized destabilization of membranes, allowing passage of macromolecules at very low concentrations. This basic knowledge is currently lacking, and is a roadblock in the design of membrane-active peptides with broad applicability. The basic knowledge that will be gained through this work will be a significant advancement in the field of membrane-active peptides. The activity that will be studied here with this award, macromolecular-sized pore formation, has not been explored thus far and its fundamental principles and mechanism of actions are unknown. Yet, it has many potential applications in biotechnology and medicine. Success in this work may enable the rational design and preparation of membrane active peptides for drug delivery and biosensing, as well as for cancer therapies, anti-viral and anti-bacterial treatments, and in agriculture for the controlled and effective release of insecticides and fungicides at very low doses. The proposed research and outreach activities will promote interest in science, exchange of knowledge, and create synergistic interactions between students and researchers at different levels in different disciplines. Technical:The goal of this project is to characterize peptides that enable macromolecules to bypass the barrier of the plasma membrane. This collaborative effort by three investigators, an engineer, a physicist and a biochemist, will delineate the sequence-structure-function relationships of two families of peptides that form large macromolecule-sized pores in bilayers at low concentrations, one of which is triggered to act only at pH less than 6.0. While such behavior is extremely rare, or perhaps non-existent in nature, the investigators have discovered, by high-throughput screening, peptides with these properties. By comparing the sequences, functions and structures of these peptides, they will uncover the fundamental principles behind the unique activity of these families. The researchers will characterize the macromolecular permeabilization by pH-insensitive and pH sensitive pore formers by performing circular dichroism, fluorescence, and atomic force microscopy measurements. They will learn how the physical properties of the lipid bilayer affect the function of the two classes of peptides, and will test specific mechanistic hypotheses with sequence variations. The work will provide many research and outreach opportunities for graduate, undergraduate and high school students, launching many new careers in science. This award by the Biomaterials Program of the Division of Materials Research in the Directorate for Physical and Mathematical Sciences (the managing program), is co-funded by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences.

非技术：该奖项下的工作将揭示ph触发和ph不敏感肽的序列和结构的基本原理，这些肽会导致大分子大小的膜不稳定，允许大分子在非常低的浓度下通过。目前缺乏这种基本知识，这是设计具有广泛适用性的膜活性肽的障碍。通过这项工作将获得的基础知识将是膜活性肽领域的重大进展。该奖项将研究的活动，大分子大小的孔隙形成，迄今尚未被探索，其基本原理和作用机制尚不清楚。然而，它在生物技术和医学方面有许多潜在的应用。这项工作的成功将有助于合理设计和制备膜活性肽，用于药物传递和生物传感，以及癌症治疗，抗病毒和抗菌治疗，以及农业中杀虫剂和杀菌剂的低剂量控制和有效释放。拟议的研究和推广活动将促进对科学的兴趣，交流知识，并在不同学科的不同层次的学生和研究人员之间建立协同互动。技术：这个项目的目标是表征肽，使大分子绕过质膜的屏障。三位研究者，一位工程师，一位物理学家和一位生物化学家，将共同努力，描绘两个多肽家族的序列-结构-功能关系，这些多肽家族在低浓度下在双层中形成大分子大小的孔隙，其中一个仅在pH值低于6.0时才会触发作用。虽然这种行为极其罕见，或者可能在自然界中不存在，但研究人员通过高通量筛选发现了具有这些特性的肽。通过比较这些肽的序列、功能和结构，他们将揭示这些家族独特活性背后的基本原理。研究人员将通过圆二色性、荧光和原子力显微镜测量来表征pH不敏感和pH敏感孔隙形成物的大分子渗透。他们将了解脂质双分子层的物理性质如何影响这两类肽的功能，并将通过序列变化测试特定的机制假设。这项工作将为研究生、本科生和高中生提供许多研究和推广机会，并在科学领域开展许多新的职业。该奖项由物理和数学科学理事会材料研究部生物材料项目（管理项目）颁发，由生物科学理事会分子和细胞生物科学部分子生物物理集群共同资助。

项目成果

Mechanism of Action of pH-Triggered, Membrane Active Peptides

pH 触发的膜活性肽的作用机制

• 发表时间: 2019
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: SY Kim, A Pittman

Conformations and Dynamic Transitions of a Melittin Derivative That Forms Macromolecule-Sized Pores in Lipid Bilayers

• DOI: 10.1021/acs.langmuir.8b00804
• 发表时间: 2018-07-17
• 期刊: LANGMUIR
• 影响因子: 3.9
• 作者: Pittman, Anna E.;Marsh, Brendan P.;King, Gavin M.
• 通讯作者: King, Gavin M.

Towards a Quantitative Understanding of Protein–Lipid Bilayer Interactions at the Single Molecule Level: Opportunities and Challenges

• DOI: 10.1007/s00232-020-00151-0
• 发表时间: 2020-11
• 期刊: The Journal of Membrane Biology
• 作者: G. King;I. Kosztin

Membrane Remodeling Induced by a pH Dependant Pore Forming Peptide via Atomic Force Microscopy

pH 依赖性成孔肽通过原子力显微镜诱导膜重塑

• 发表时间: 2019
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: A Pittman, SY Kim

Conformations and Dynamic Transitions of a Melittin Derivative in Lipid Bilayer

蜂毒肽衍生物在脂质双层中的构象和动态转变

• DOI: 10.1016/j.bpj.2017.11.2505
• 发表时间: 2018
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Pittman, Anna E.;King, Gavin M.
• 通讯作者: King, Gavin M.