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Assessing Genetic Algorithm-Based Docking Protocols for Prediction of Heparin Oligosaccharide Binding Geometries onto
Samuel G Holmes1,2, Umesh R Desai1,2
1Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract:
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.
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