ABI Innovation: Development of Glycan Modeling and Simulation Toolset

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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.