ABI Innovation: Development of Glycan Modeling and Simulation Toolset

碳水化合物是糖或糖链，也被称为聚糖。它们可以共价地附着在蛋白质（糖蛋白）和脂质（糖脂）上，或者以小的可溶性分子的形式存在。研究聚糖的实验技术并不像研究其他类型的生物分子那样发达，包括缺乏计算工具。这意味着很难确定哪些聚糖有助于蛋白质功能，它们如何调节这种功能，以及如何修改它们以优化有趣的特性。蛋白质的结构记录，包括糖基化蛋白质，在蛋白质数据库（PDB）中出现的数量越来越多。通过使用复杂的计算工具选择这些糖基化蛋白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理解生物作用，又可以自下而上地模拟原子水平上的结构波动；后者提供了非常深入的了解不同的聚糖如何影响修饰蛋白质的折叠和功能。此外，细胞膜上的大多数蛋白质都是糖基化的，这对细胞识别和信号传导很重要；CHARMM-GUI Membrane Builder工具集提供了更逼真的生物膜建模，将进一步丰富膜结构模拟的可用库。本项目旨在通过开发一个全面的聚糖建模和仿真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，该项目将通过发表研究成果和参加研讨会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，用于模拟和模拟含聚糖的生物系统，并在糖蛋白、糖脂和蛋白质-聚糖复合物的背景下，深入了解聚糖的结构、动力学和功能。一个全面的工具集的计算分析，建模和模拟糖缀合物和聚糖相关的配合物将被开发。该工具集将包括(1)Glycan Modeler，用于从蛋白质连接的聚糖的初级序列预测其结构的工具；(2) GLYSUM， GLYcan单糖替代矩阵，相当于BLOSUM矩阵的聚糖；(3) GLDB, Glycan Ligand Database，用于方便地检索蛋白质-聚糖相互作用模式和PDB中的基序；(4) GBS- predictor，一种基于模板的工具，用于预测目标蛋白中潜在的聚糖结合位点（GBS）；(5)含糖脂膜构建器（glycolids -containing Membrane Builder），用于构建含糖脂的复杂膜系统的直观工具。该项目还寻求通过提供相关工具（http://www.glycanstructure.org和http://www.charmm-gui.org），促进关于聚糖结构、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.