ABI Innovation: Development of Glycan Modeling and Simulation Toolset

碳水化合物是糖或糖链，也被称为多糖。它们可以共价连接到蛋白质(糖蛋白)和脂类(糖脂)上，也可以作为小的、可溶的分子存在。研究葡聚糖的实验技术没有其他类型的生物分子那么发达，包括缺乏计算工具。这意味着很难决定哪些多糖对蛋白质功能有贡献，它们如何调节这一功能，以及如何对它们进行修饰以优化有趣的特性。蛋白质数据库(PDB)中出现了越来越多的蛋白质结构记录，包括糖基化蛋白质。通过使用复杂的计算工具选择这些糖基化蛋白质结构进行更深入的研究，可以建立一种基于知识的方法来理解它们的结构、功能和生物学作用之间的关系。基于知识的方法既可以自上而下地了解生物角色，也可以自下而上地模拟原子水平的结构波动；后者提供了非常深入的洞察，了解不同的多糖如何影响修饰蛋白质的折叠和功能。此外，细胞膜中的大多数蛋白质都是糖基化的，这对细胞识别和信号传递很重要；CHARMM-图形用户界面膜生成器工具集提供的更逼真的生物膜建模将进一步丰富现有的膜结构模拟技术。该项目旨在通过开发用于多糖建模和模拟的综合工具集来实现这些目标。研究生和本科生都将接受跨学科计算结构糖生物学的培训。特别是，该项目将通过出版研究成果和参加讲习班来提高研究界的科学素养。该项目的主要目标是开发一个计算工具集，用于模拟和模拟含糖的生物系统，并在糖蛋白、糖脂和蛋白质-多糖复合体的背景下，获得对糖的结构、动力学和功能的深入和分子水平的了解。将开发一套全面的工具包，用于计算分析、建模和模拟糖共轭化合物和与糖相关的络合物。这套工具将包括(1)Glycan Modeler，一个根据蛋白质连接的葡聚糖的一级序列预测其结构的工具；(2)GLYSUM，葡聚糖单糖替代矩阵，相当于Blosum基质的葡聚糖；(3)GLDB，葡聚糖配体数据库，用于方便地检索PDB中的蛋白质-葡聚糖相互作用模式和基序；(4)GBS-Predictor，一个基于模板的工具，用于预测目标蛋白质中潜在的糖结合位点(GBS)；以及(5)含糖脂的膜构建器，它是一个直观的工具，用于构建包含糖脂的复杂膜系统。该项目还寻求通过提供http://www.glycanstructure.org和http://www.charmm-gui.org.工具来促进关于多糖结构、动力学和功能的协同科学研究和教育

Carbohydrates are sugars or chains of sugars that are also referred to as glycans. They can can be covalently attached to proteins (glycoproteins) and lipids (glycolipids), or exist as small, soluble molecules. Experimental techniques for studying glycans are not as well developed as for other types of biomolecules, including a lack of computational tools. This means it can be hard to decide which glycans contribute to protein function, how they act to modulate this function, and how to modify them to optimize interesting properties. Structural records of proteins, including glycosylated proteins, are appearing in ever larger numbers in the Protein Data Bank (PDB). By selecting these glycosylated protein structures for deeper investigation with sophisticated computational tools, a knowledge-based approach to understanding the relationship between their structure, function and biological roles can be built. Knowledge based approaches allow both top-down understanding of biological roles, and bottom-up simulations of structural fluctuations at the atomic level; the latter provide very deep insight into how different glycans affect the folding and function of modified proteins. In addition, most proteins in cell membranes are glycosylated, which is important to cell recognition and signaling; more realistic modeling of biological membranes, provided by the CHARMM-GUI Membrane Builder toolset, will further enrich the available repertoire of membrane structure simulations. This project aims to achieve these goals by developing a comprehensive toolset for glycan modeling and simulation. Both graduate and undergraduate students will be trained in the interdisciplinary computational structural glycobiology. In particular, this project will raise the scientific literacy of the research community through the publication of research results and workshop participation. The main objective of this project is to develop a computational toolset for modeling and simulation of glycan-containing biological systems and to acquire an in-depth and molecular-level understanding of glycan structure, dynamics, and function in the context of glycoproteins, glycolipids, and protein-glycan complexes. A comprehensive toolset for the computational analysis, modeling, and simulation of glycoconjugates and glycan-associated complexes will be developed. This tool set will include (1) Glycan Modeler, a tool for structure prediction of protein-linked glycans from their primary sequences; (2) GLYSUM, the GLYcan monosaccharide SUbstitution Matrix, the glycan equivalent to the BLOSUM matrix; (3) GLDB, Glycan Ligand Database for easy retrieval of protein-glycan interaction patterns and motifs in the PDB; (4) GBS-Predictor, a template-based tool to predict potential glycan binding sites (GBS) in a target protein; and (5) glycolipid-containing Membrane Builder, an intuitive tool to build a complex membrane system containing glycolipids. This project also seeks to foster synergistic scientific research and education on glycan structure, dynamics, and function by making resulting tools available http://www.glycanstructure.org and http://www.charmm-gui.org.