Collaborative Research: CIBR: Computational resources for modeling and analysis of realistic cell membranes

生物膜是将活细胞与环境分离并产生细胞内隔室的半渗透屏障。它们由许多类型的脂质组成，并挤满了许多跨膜和外周膜蛋白。这些蛋白质参与所有重要的细胞过程，包括生物发生、能量和信号转导、分子运输、囊泡运输、细胞运动、识别、粘附和形状调节。尽管膜蛋白的原子结构越来越多，但缺乏关于其在天然膜中的空间位置和蛋白质-脂质相互作用的信息阻碍了我们对其折叠、稳定性、功能和调节的分子机制的理解。出于对蛋白质在具有天然脂质成分的非平面和可变形膜中的现实表示的不断增长的需求，我们提出创建一个高容量的网络基础设施，用于快速和可重复地组装膜蛋白与天然脂质，以构建灵活的多组分生物膜，用于随后的结构分析和分子动力学（MD）模拟。该项目将通过培训计算机科学专业的学生开发生物信息学资源，利用开发的教学工具箱，通过为学生和用户社区提供培训材料和基于网络的研讨会，以促进膜模拟的研究经验。这个合作项目将加强和联合收割机的高度认可和广泛使用的PPM/OPM和CHARMM的能力，图形用户界面资源，已开发的研究小组从密歇根大学和利哈伊大学。该项目有三个主要组成部分。首先，将提出PPM（蛋白质在膜中的定位）方法，用于计算具有不同极性分布、不对称性、电荷和曲率特征的可变形膜中蛋白质的空间排列和结合能。第二，一个新的PPM/CHARMM-GUI工具箱将开发通过集成改进的PPM方法和CHARMM-GUI膜构建器组装天然类蛋白质-脂质系统，并提供输入文件，通过各种MD模拟软件包的生物膜的逼真模拟。基于网络的开放平台将允许不同专业知识的用户轻松设置和执行具有复杂脂质组成的可变形膜中已知三维（3D）结构的膜蛋白的模拟。第三，将使用该工具箱生产用于数千种已知膜蛋白结构的天然全原子膜系统，这些膜蛋白结构具有来自真核和原核细胞和细胞器的天然脂质。所产生的蛋白质-脂质系统连同MD模拟的输入将被存放在改进和扩展的OPM数据库（在opm.phar.umich.edu）中。这些输入可以直接用于最先进的真实细胞膜的MD模拟，以帮助规划和解释实验研究。拟议的工具箱（charmm-gui.org）将显著增强现有网络资源的生物分子模拟能力，同时确保期待已久的过渡，从只模拟跨膜蛋白到模拟跨膜和外周蛋白及其膜复合物;从人工脂质到生物分子模拟。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

Biological membranes are semi-permeable barriers that separate living cells from the environment and create intracellular compartments. They are composed of many types of lipids and are crowded with numerous transmembrane and peripheral membrane proteins. These proteins participate in all vital cellular processes, including biogenesis, energy and signal transduction, molecular transport, vesicular trafficking, cell motility, recognition, adhesion, and shape regulation. Despite the growing number of atomic structures of membrane proteins, the lack of information about their spatial positions and protein-lipid interactions in their native membranes impedes our understanding of molecular mechanisms of their folding, stability, function, and regulation. Motivated by rising demands in realistic representation of proteins in non-planar and deformable membranes with natural lipid compositions, we propose a creation of a high-capacity cyberinfrastructure for fast and reproducible assembly of membrane proteins with natural lipids to build flexible multicomponent biomembranes for subsequent structural analysis and molecular dynamics (MD) simulations. This project will promote synergy between scientific research and education by training computer science students in developing bioinformatics resources, by using the developed toolbox for teaching, and by providing training materials and web-based workshops for students and the user community to promote research experience in membrane simulations.This collaborative project will enhance and combine capabilities of the highly recognized and widely used PPM/OPM and CHARMM-GUI resources that have been developed by the research teams from the University of Michigan and Lehigh University. The project has three main components. First, the PPM (Positioning of Proteins in Membranes) method will be advanced for calculating the spatial arrangement and binding energy of proteins in deformable membranes characterized by diverse polarity profiles, asymmetry, charge, and curvature. Second, a new PPM/CHARMM-GUI toolbox will be developed by integrating the improved PPM method and CHARMM-GUI Membrane Builder to assemble native-like protein-lipid systems and provide input files for realistic simulations of biomembranes by various MD simulation packages. The open web-based platform will allow users of diverse expertise to easily setup and perform simulations of membrane proteins with known three-dimensional (3D) structures in deformable membranes with complex lipid composition. Third, native-like all-atom membrane systems for thousands of known membrane protein structures with natural lipids from eukaryotic and prokaryotic cells and organelles will be produced using this toolbox. The generated protein-lipid systems together with the inputs for MD simulations will be deposited in the improved and expanded OPM database (at opm.phar.umich.edu). These inputs can be directly used for state-of-the-art MD simulations of realistic cell membranes to assist in planning and interpreting experimental studies. The proposed toolbox (at charmm-gui.org) will significantly enhance the capacity of existing web resources for biomolecular simulations, while ensuring the long-awaited transition from modeling only transmembrane proteins to simulations of both transmembrane and peripheral proteins and their complexes in membranes; from artificial lipidThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.