title: A computational approach for deciphering the organization of glycosaminoglycans.
abstract: BACKGROUND
  Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers.
  
  
  RESULTS
  To address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts.
  
  
  CONCLUSIONS
  This model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America. spencerj@bu.edu
authors.forename: Jean L
authors.initials: JL
authors.lastname: Spencer
authors.forename: Joel A
authors.initials: JA
authors.lastname: Bernanke
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Buczek-Thomas
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nugent
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D004187:Disaccharides / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology; D005583:Fourier Analysis; D006025:Glycosaminoglycans / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D019763:Heparin Lyase / Q000378:metabolism; D006497:Heparan Sulfate / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D006603:Hexuronic Acids / Q000032:analysis / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D012984:Software; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D004187:Disaccharides; D006025:Glycosaminoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate; D006603:Hexuronic Acids