Modeling Protein–Glycosaminoglycan Complexes: Does the Size Matter?

Abstract

Docking glycosaminoglycans (GAGs) has been challenging because of the complex nature of these long periodic linear and negatively charged polysaccharides. Although standard docking tools like Autodock3 are successful when docking GAGs up to hexameric length, they experience challenges to properly dock longer GAGs. Similar limitations concern other docking approaches typically developed for docking ligands of limited size to proteins. At the same time, most of more advanced docking approaches are challenging for a user who is inexperienced with complex in silico methodologies. In this work, we evaluate the binding energies of complexes with different lengths of GAGs using all-atom molecular dynamics simulations. Based on this analysis, we propose a new docking protocol for long GAGs that consists of conventional docking of short GAGs and further elongation with the use of a coarse-grained representation of the GAG parts not being in direct contact with its protein receptor. This method automated by a simple script is straightforward to use within the Autodock3 framework but also useful in combination with other standard docking tools. We believe that this method with some minor case-specific modifications could also be used for docking other linear charged polymers.

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

“…In fact, recent studies on large number of GAG disaccharides have further confirmed the classic works by Mulloy and co-workers [31] that glycosidic torsions Φ and Ψ vary within a relatively small range irrespective of sulfation pattern [39] , [40] . This gives rise to the canonical ‘helical’ topology of Hp/HS chains, which is used as the primary Hp/HS topology in docking [41] , [42] , [43] , although pucker and glycosidic bond flexibility is typically allowed in these studies [44] , [45] . Yet, Hp/HS chains are thought to be linear cylinders, which implies that “sulfation code” is wholly configurational with only a marginal room for IdoA conformations.…”

Molecular architecture and platelet-activating properties of small immune complexes assembled on intact heparin and their possible involvement in heparin-induced thrombocytopenia

“…The favorable flexibility parameters of the heparin chains and their high charge density suggest that the “wrap-around” mode of PF4/heparin interactions is favored thermodynamically, which is also confirmed by the results of MD simulations ( Figure 3 ). Although the MD simulations carried out in this study were not intended to explore the entire conformational space available to PF4/heparin complexes (explicit modeling remains problematic for GAG chains above decamers 28,36,37 ), they certainly demonstrate that the “wrap-around” mode of association is feasible. At the same time, one must also consider a possibility of kinetic effects preventing formation of structures that maximize the electrostatics-driven enthalpic gains.…”

Glycosaminoglycans: What Remains To Be Deciphered?

“…It represents a substantial limitation in translating the results of the computational prediction to biological processes at larger scales. 127 Experimentally, this limitation is mainly due to the lack of available well-characterized longer oligosaccharides and full-length GAGs and the subsequent limitation of 3D structures of GAG–proteins complexes (currently more than 120 PDB entries, including less than 40 nonredundant nonenzymatic complexes). 110 Computational methods to tackle long polysaccharide chains are deficient because running MD simulations for many sequences remains challenging, especially at a high-throughput level.…”

“…About 90% of the studies have been performed with short GAG oligosaccharides (< DP5). It represents a substantial limitation in translating the results of the computational prediction to biological processes at larger scales . Experimentally, this limitation is mainly due to the lack of available well-characterized longer oligosaccharides and full-length GAGs and the subsequent limitation of 3D structures of GAG–proteins complexes (currently more than 120 PDB entries, including less than 40 nonredundant nonenzymatic complexes) .…”