A Bittersweet Computational Journey among Glycosaminoglycans

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge.

HIV-1 Tat and Heparan Sulfate Proteoglycans Orchestrate the Setup of in Cis and in Trans Cell-Surface Interactions Functional to Lymphocyte Trans-Endothelial Migration

“…Subsequent docking studies were then performed between the Tat homodimer and heparin, used here as a structural analogue of the GAG chains of HSPGs [45]. By means of the sliding window method [47], we succeeded in obtaining a model of two separate 12-mer heparin chains that bind the two monomers of the Tat homodimer, in agreement with the in trans HSPG/Tat-Tat/HSPG quaternary complex [6].…”

“…We finally exploited molecular modelling and docking of the interaction of monomeric and homodimeric Tat with heparin in order to gain further insight into the Tat/HSPG interaction, paying attention to the surface exposure of the various Tat functional domains, including the cysteine-rich region, the basic region and the RGD integrin-binding motif. Due to its structural analogies with HS, heparin has been widely used in computational studies as a surrogate to gain insight into the binding of numerous HSPG/protein complexes [45].…”

Multifaceted Computational Modeling in Glycoscience

“…These interactions mediate their biological activities and play essential roles in physiopathological processes such as growth factor control, anticoagulation, hemostasis, and cell adhesion. , New data are being integrated to complement the investigation of the integration of glycosaminoglycans . As part of the interactions between proteins and GAGs imply electrostatic interactions, it is indispensable to consider solvent for the interactions, but the impact of solvation/desolvation on complex formation is difficult to assess. , Moreover, the challenge remains to identify well-defined and predicted GAG-binding pockets on bound proteins. , …”

Advanced Molecular Dynamics Approaches to Model a Tertiary Complex APRIL/TACI with Long Glycosaminoglycans

“…Despite the recent advances in molecular docking of glycosaminoglycan (GAG) oligosaccharides, it still remains a challenge to dock longer GAGs [ 1 ]. The main reason for this is the physical–chemical nature of GAGs.…”

“…Although GAG’s certain binding specificity has been observed in several biologically relevant systems [ 7 , 8 , 9 ], protein–GAG interactions are often predominantly electrostatics-driven, and their binding energies correlate with the GAG net charge [ 10 , 11 , 12 , 13 ]. Despite the fact that computational studies of GAGs persist as a general challenge due to the required conformational sampling and their periodicity, there are numerous successful studies on proteins complexes with shorter GAG oligosaccharides (of length up to octasaccharides) [ 1 , 14 , 15 , 16 , 17 , 18 ]. On the other hand, there are very few studies that focus on longer GAG molecules in complexes with proteins.…”