ABI Innovation: Development of Glycan Modeling and Simulation Toolset

碳水化合物是糖或糖链，也称为聚糖。它们可以共价连接到蛋白质（糖蛋白）和脂质（糖脂），或作为小的可溶性分子存在。研究聚糖的实验技术不如其他类型的生物分子发达，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，以及如何修饰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。通过选择这些糖基化蛋白质结构进行更深入的研究与复杂的计算工具，一个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可以建立。基于知识的方法既允许自上而下的理解生物学作用，又允许自下而上的模拟原子水平上的结构波动;后者提供了对不同聚糖如何影响修饰蛋白质的折叠和功能的非常深入的了解。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导很重要; CHARMM-GUI Membrane Builder工具集提供的更逼真的生物膜建模将进一步丰富可用的膜结构模拟库。该项目旨在通过开发一个全面的聚糖建模和模拟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用于含聚糖生物系统建模和模拟的计算工具集，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，建模和模拟的糖复合物和聚糖相关的复合物将被开发。该工具集将包括（1）聚糖建模器，一种用于从蛋白质连接聚糖的一级序列预测其结构的工具;（2）GLYSUM，聚糖单糖取代矩阵，相当于BLOSUM矩阵的聚糖;（3）GLDB，聚糖配体数据库，用于轻松检索PDB中的蛋白质-聚糖相互作用模式和基序;（4）GBS-预测器，一种基于模板的工具，用于预测靶蛋白中的潜在聚糖结合位点（GBS）;以及（5）含糖脂的膜构建器，一种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所产生的工具来促进关于聚糖结构、动力学和功能的协同科学研究和教育，http://www.glycanstructure.org和http://www.charmm-gui.org。

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.