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

生物膜是将活细胞与环境隔开并在细胞内形成隔间的半透屏障。它们由多种类型的脂类组成，并挤满了大量的跨膜和外周膜蛋白。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、黏附和形状调节。尽管膜蛋白的原子结构越来越多，但缺乏关于它们在天然膜上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。在非平面和具有天然脂组成的可变形膜中真实表达蛋白质的需求日益增长的推动下，我们提出了一种高容量的网络基础设施，用于膜蛋白与天然脂的快速和可重复组装，以构建灵活的多组分生物膜，用于后续的结构分析和分子动力学(MD)模拟。这个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，使用开发的教学工具箱，并通过为学生和用户社区提供培训材料和网络研讨会来促进膜模拟的研究经验，促进科学研究和教育之间的协同。这个合作项目将增强和结合由密歇根大学和利哈伊大学的研究团队开发的高度认可和广泛使用的PPM/OPM和CHARMM-图形用户界面资源的能力。该项目有三个主要组成部分。首先，将提出PPM(Posiating Of Proteins In Memages)方法来计算蛋白质在具有不同极性分布、不对称性、电荷和曲率的可变形膜中的空间排列和结合能。其次，将改进的PPM方法与CHARMM-GUI膜构建器相结合，开发一个新的PPM/CHARMM-GUIUS工具箱，用于组装天然类蛋白质-脂质系统，并为各种MD模拟软件对生物膜的逼真模拟提供输入文件。这个开放的基于网络的平台将允许具有不同专业知识的用户轻松地设置和执行具有已知三维(3D)结构的膜蛋白的模拟，这些膜蛋白位于具有复杂脂质成分的可变形膜中。第三，使用该工具箱将生产数千种已知膜蛋白结构的天然类全原子膜系统，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类。生成的蛋白质-脂肪系统连同MD模拟的输入将存放在改进和扩展的OPM数据库(opm.phar.umich.edu)中。这些输入可以直接用于现实细胞膜的最先进的MD模拟，以帮助计划和解释实验研究。拟议的工具箱(位于charmm-gui.org)将显著增强现有网络资源用于生物分子模拟的能力，同时确保期待已久的从仅模拟跨膜蛋白质过渡到模拟跨膜和外周蛋白质及其在膜中的复合体；来自人造脂该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.