权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ABI innovation: Computational method for exploring the mysteries of cell-penetrating peptides

ABI创新：探索细胞穿膜肽奥秘的计算方法

基本信息

批准号：
1458002
负责人：
Andrei Lomize
金额：
$ 75.47万
依托单位：
Regents of the University of Michigan - Ann Arbor
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1458002&HistoricalAwards=false
关键词：
ABI innovation Computational method exploring

项目摘要

This project aims to develop a new computational method and a web server for prediction of the cell-penetrating ability of naturally-occurring and synthetic peptides and analysis of their interactions with cellular membranes. Cell-penetrating peptides (CPPs) were discovered two decades ago and since then were used for delivery of various macromolecules into cells and tissues. However, the molecular mechanisms of passage of peptides through cell membranes still remain a mystery. To shed light on the mechanisms of direct membrane crossing by CPPs, an innovative theoretical method will be developed. This method will quantify the energetics of the processes underlying peptide entry into cells, including binding of peptides to membranes, their folding into alpha-helical and beta-sheet structures, and crossing the lipid bilayer by diffusion or by inducing membrane deformations, such as thinning, curving, or pore formation. The project is expected to have a significant scientific impact by providing unique methodology and the first public web server for discovery and design of novel CPPs. This method will be also valuable for analysis of interactions with membranes of a much wider spectrum of biologically active peptides and proteins with potentially beneficial or harmful physiological effects. The development and application of such general tool will advance scientific knowledge in the field of membrane peptides and proteins. An easy-to-use web tool will benefit a broad community of students, teachers and researchers engaged in the fields of biophysics, molecular and cell biology, bio-nanotechnology, and drug design. The project includes participation of students from the University of Michigan in development of the computational resources, as well as teaching K-12 students from socio-economically disadvantaged groups using videos, images, and tangible molecular models of peptides and proteins in membranes.The new method will combine a thermodynamic model of secondary structure formation by peptides and an anisotropic solvent model of the lipid bilayer that accounts for specific polarity profiles, curvature, elastic moduli, and transmembrane potential in different biological membranes. The proposed methodology will be extensively tested and implemented on a public web server that will allow the following: (1) to quantify membrane-peptide interactions, energy and binding modes, including deformations of the lipid bilayer by peptides (PPM 3.0); (2) to perform modeling of membrane-bound beta-sheets and alpha-helices, including generation and optimization of their all-atom three-dimensional structures (FMAP 2.0); and (3) to predict potential CPPs by calculating and evaluating their possible translocation mechanisms, pathways and energy barriers in the lipid bilayer (CPPpred). The CPPpred server will generate all-atom three-dimensional structures of peptides, estimate their membrane binding modes and energy barriers along the translocation pathway, and evaluate mechanisms of peptide translocation using their amino acid sequence and parameters of specific membranes as input. The high computational efficiency of the method will allow its application for large-scale computational screening of peptide databases to identify potential CPPs.

本项目旨在开发一种新的计算方法和网络服务器，用于预测天然和合成肽的细胞穿透能力，并分析它们与细胞膜的相互作用。细胞穿透肽（CPP）是二十年前发现的，从那时起被用于将各种大分子递送到细胞和组织中。然而，肽通过细胞膜的分子机制仍然是一个谜。为了阐明CPP直接跨膜的机制，将开发一种创新的理论方法。该方法将量化肽进入细胞的潜在过程的能量学，包括肽与膜的结合，它们折叠成α-螺旋和β-折叠结构，以及通过扩散或通过诱导膜变形（例如变薄、弯曲或孔形成）穿过脂质双层。该项目预计将通过提供独特的方法和第一个用于发现和设计新型CPP的公共Web服务器来产生重大的科学影响。该方法对于分析具有潜在有益或有害生理效应的更广谱的生物活性肽和蛋白质与膜的相互作用也将是有价值的。这种通用工具的开发和应用将促进膜肽和蛋白质领域的科学知识。一个易于使用的网络工具将有利于广大社区的学生，教师和研究人员从事生物物理学，分子和细胞生物学，生物纳米技术和药物设计领域。该项目包括密歇根大学的学生参与开发计算资源，以及使用视频，图像，新方法将结合联合收割机的热力学模型的二级结构形成的肽和各向异性溶剂模型的脂双层，占不同生物膜中的特定极性分布、曲率、弹性模量和跨膜电位。所提出的方法将在一个公共网络服务器上进行广泛的测试和实施，这将允许：（1）量化膜-肽相互作用，能量和结合模式，包括肽对脂质双层的变形（PPM 3.0）;（2）进行膜结合β-折叠和α-螺旋的建模，包括它们的全原子三维结构的生成和优化（FMAP 2.0）;（3）通过计算和评估可能的易位机制来预测潜在的CPP，脂质双层中的通道和能量势垒（CPPpred）。CPPpred服务器将生成肽的全原子三维结构，估计它们的膜结合模式和沿着易位途径的能垒，并使用它们的氨基酸序列和特定膜的参数作为输入来评估肽易位的机制。该方法的高计算效率将允许其应用于肽数据库的大规模计算筛选以识别潜在的CPP。