**1. Structure and Imaging**

The structural heterogeneity of GAGs complicates the composition and sequence analysis of GAGs. No less than 200 different monosaccharides have been identified; this has resulted in a very high number of disaccharide segments exhibiting high conformational flexibility. In addition, there have also been intrinsic difficulties in establishing the threedimensional structures of GAGs. Despite these difficulties and recognizing that the shape of molecules is a fundamental principle in chemistry, physics, and biology, scientists are developing experimental and computational tools to elucidate and understand molecular shapes and molecular motions. Elisabeth Whitmore and collaborators [4] report on the development of efficient atomic resolution models using molecular GAG dynamics. They illustrate the outcome of their application for the case of non-sulfated chondroitin, which may provide insights and arguments for the understanding of disciplines where molecular dynamics play a crucial role.

There is a healthy dialogue between computational and experimental endeavors, a typical example being the structural determination of the oligo of GAGS and polysaccharides and their interactions with proteins. Results have accumulated over time due to X-ray singlecrystal diffraction methods, X-ray fiber diffractometry, solution NMR spectroscopy, and scattering data. These data have been curated, annotated, and organized before their structuration into a three-dimensional database containing three-dimensional data on GAGs and GAGs–protein complexes retrieved from the PDB [5]. The database includes protein sequences and the standard nomenclature for GAG composition, sequence, and topology. It provides a family-based classification of GAGs that is cross-referenced with glyco-databases with links to UniProtKB via accession numbers. The 3D visualization of contacts between GAGs and their protein ligands is implemented via the protein–ligand interaction profiler (PLIP). The nature of the structure that GAG polysaccharides can adopt, either solid-state or solution, is also reported. Finally, characterized quaternary structures of the complexes

improve our understanding as to if and how GAGs participate in long-range, multivalent binding with potential synergy when several chains are involved in interactions.

Molecular interactions involving GAGs are not restricted to proteins. Many authors consider the large GAG polymeric backbones and their chemical properties to be essential features for the rational design of drug delivery and diagnostic systems. Magnetic resonance imaging is an established diagnostic method for which GAGs, when adequately decorated, offer the benefit of contrast enhancers.

The administration of a paramagnetic contrast agent, such as a metal chelate, such as gadolinium diethylene triamine penta-acetic acid (Gd-DTPA), helps visualize relative GAG distribution in vivo. For example, the negative charge of the contrast agent will distribute itself within articular cartilage in a spatially inverse relationship to the concentration of negatively charged GAG molecules. Alfonso Ponsiglione and collaborators [6] explore the range of advantages that could represent fine control over the combination of GAGs and imaging agents in the formulation of novel multifunctional diagnostic probes.
