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Understanding Glycosaminoglycan – Protein Specificity Through Computational Approaches

Glycosaminoglycans – protein interactions modulate a number of physiological processes such as coagulation, immune response, angiogenesis, morphogenesis and pathogen infection. Yet, a majority of these interactions involve allosteric regulation of protein and are poorly understood. We have developed a genetic algorithm‐based combinatorial virtual screening approach to understand the nature of interaction of glycosaminoglycans with proteins. A dual‐filter strategy employing an ‘affinity’ filter followed by a ‘specificity’ filter rapidly sorted the combinatorial library into distinct groups of sequences. Application of this strategy on a library of 46,000 sequences resulted in identification of only five sequences that recognize heparin cofactor II with ‘high‐affinity and high‐specificity’. Likewise, the strategy led to the prediction of a novel geometry for dermatan sulfate hexasaccharide onto heparin cofactor II, which explained the formation of the ternary glycosaminoglycan – heparin cofactor II – protease complex. The strategy represents a general approach for understanding specificity of allosteric glycosaminoglycan – protein interactions and may lead to the design of novel allosteric agonists or antagonists of proteins.