Simulation studies of the mechanism of translocation of cell penetrating peptides

细胞穿膜肽易位机制的模拟研究

• 批准号: 8147679
• 负责人: Angel E Garcia
• 金额: $ 30.38万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147679
• 关键词: Amino Acids; Antimicrobial Cationic Peptides; Arginine; Biological; Cell Communication; Cell membrane; Cells; Charge; Chemicals; Collaborations; Data; Dependence; Development; Diffuse; Diffusion; Drug Delivery Systems; Endocytic Vesicle; Eukaryota; France; HIV; Image; Imaging Techniques; Iowa; Lead; Length; Lipid Bilayers; Lipids; Mechanics; Mediating; Membrane; Membrane Potentials; Modeling; Molecular; Molecular Models; Nucleic Acids; Peptide Nucleic Acids; Peptides; Phospholipids; Property; Proteins; Research; Side; Structure; Surface; System; Techniques; Testing; Therapeutic; antimicrobial peptide; base; cellular imaging; density; design; dosage; inorganic phosphate; macromolecule; molecular dynamics; molecular modeling; molecular size; protein aminoacid sequence; public health relevance; research study; simulation; uptake; vector; working group

DESCRIPTION (provided by applicant): Cell penetrating peptides (CPP) are highly cationic, hydrophilic, short, peptides capable of translocating across the cell membrane. These peptides have the special property of carrying with them cargoes of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. It is anticipated that the further development and refinement of CPP techniques will provide drug delivery vectors, cellular imaging techniques, and molecular therapeutics. The objective of the proposed research is to develop an atomic level model of the mechanism and energy of translocation of these peptides across lipid bilayers. This model will provide the basis of further development of CPP sequences that effectively translocate across cell membranes. We will also study the effect secondary structure and sequence on the interaction of the CPP peptides with membranes. These studies will help us design new sequences that will translocate more efficiently, and will therefore require smaller dosage of CPPs. We also postulate that some cationic antimicrobial peptides (AMP), like protegin-1, will insert into the lipid bilayer by a mechanism that shares many features with the mechanism of translocation of cell penetrating peptides. We will study the interaction of PG-1 with model lipid bilayers that mimic bacterial and eukaryote cell membranes to understand the selectivity of AMP to bacterial cells. Our studies are based on extensive molecular dynamics simulations and molecular modeling. Our research may lead to the development of better cell penetrating peptides and new antimicrobial peptides. PUBLIC HEALTH RELEVANCE: Cell penetrating peptides have the special property of carrying with them cargos of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. This project aims at developing an atomic level description of the up to now elusive mechanism of translocation of these peptides across cells. The elucidation of this mechanism will enable the development of more efficient delivery vectors for imaging and therapeutic purposes.

描述（由申请方提供）：细胞穿透肽（CPP）是能够跨细胞膜转运的高度阳离子、亲水性短肽。这些肽具有携带大范围分子大小的货物的特殊性质，例如蛋白质、核酸、肽核酸和其他生物和非生物分子。这些肽已被广泛研究，作为将大分子递送至细胞用于治疗目的的手段。预计CPP技术的进一步发展和完善将提供药物递送载体、细胞成像技术和分子治疗。拟议的研究的目的是开发一个原子水平的模型的机制和能量的易位这些肽跨脂质双层。该模型将为进一步开发有效跨细胞膜转运的CPP序列提供基础。我们还将研究二级结构和序列对CPP肽与膜相互作用的影响。这些研究将帮助我们设计新的序列，将更有效地易位，因此将需要更小剂量的CPP。我们还假设，一些阳离子抗菌肽（AMP），如protegin-1，将插入到脂质双层的机制，共享许多功能的细胞穿透肽的易位机制。我们将研究PG-1与模拟细菌和真核生物细胞膜的模型脂质双层的相互作用，以了解AMP对细菌细胞的选择性。我们的研究是基于广泛的分子动力学模拟和分子建模。我们的研究可能会导致更好的细胞穿透肽和新的抗菌肽的开发。 公共卫生关系：细胞穿透肽具有携带各种分子大小的货物的特殊性质，如蛋白质、核酸、肽核酸和其他生物和非生物分子。这些肽已被广泛研究，作为将大分子递送至细胞用于治疗目的的手段。这个项目的目的是发展一个原子水平的描述到目前为止难以捉摸的机制易位这些肽跨细胞。这一机制的阐明将使更有效的成像和治疗目的的载体的发展。