Assessing Genetic Algorithm-Based Docking Protocols for Prediction of Heparin Oligosaccharide Binding Geometries onto Proteins

Although molecular docking has evolved dramatically over the years, its application to glycosaminoglycans (GAGs) has remained challenging because of their intrinsic flexibility, highly anionic character and rather ill-defined site of binding on proteins. GAGs have been treated as either fully rigid or fully flexible in molecular docking. We reasoned that an intermediate semi-rigid docking (SRD) protocol may be better for the recapitulation of native heparin/heparan sulfate (Hp/HS) topologies. Herein, we study 18 Hp/HS-protein co-complexes containing chains from disaccharide to decasaccharide using genetic algorithm-based docking with rigid, semi-rigid, and flexible docking protocols. Our work reveals that rigid and semi-rigid protocols recapitulate native poses for longer chains (5 -> 10 mers) significantly better than the flexible protocol, while 2 -> 4-mer poses are better predicted using the semi-rigid approach. More importantly, the semi-rigid docking protocol is likely to perform better when no crystal structure information is available. We also present a new parameter for parsing selective versus non-selective GAG-protein systems, which relies on two computational parameters including consistency of binding (i.e., RMSD) and docking score (i.e., GOLD Score). The new semi-rigid protocol in combination with the new computational parameter is expected to be particularly useful in high-throughput screening of GAG sequences for identifying promising druggable targets as well as drug-like Hp/HS sequences.

Automated summary

Although molecular docking remains challenging for glycosaminoglycans (GAGs) due to their flexibility and anionic character, using a semi-rigid docking protocol can better reproduce the native topology of heparin/heparan sulfate (Hp/HS). Rigid and semi-rigid protocols are more accurate in predicting longer chain poses, while the semi-rigid approach is better for 2-4-mer poses. The new semi-rigid protocol, combined with a new computational parameter, shows promising potential for high-throughput screening of GAG sequences and identifying drug targets and drug-like Hp/HS sequences.