Computational insights into heparin-small molecule interactions: Evaluation of the balance between stacking and...

Glycosaminoglycans (GAGs), anionic periodic linear polysaccharides, are involved in a manifold of key biochemical processes ongoing in the extracellular matrix via establishing direct intermolecular interactions with diverse classes of biopolymers as well as with bioactive small molecules. Due to their acidic nature, they are capable of binding positively charged ligands, which, in turn could affect their binding with protein and peptide targets, modulating a number of physiologically important signaling pathways. Therefore, it is of great significance to improve our understanding on the molecular basis underlying GAG-small molecule interactions. In this study, we applied in silico approaches (molecular dynamics and free energy calculations) complemented with circular dichroism and absorption spectroscopy to characterize the complex formation between heparin, one of the principal members of GAG family, and twenty different cationic ligands including therapeutic drugs, alkaloids and organic dyes. In particular, the oligomerization propensity of ligands prior to heparin binding, binding free energy parameters, effects of the ionic strength are rigorously described. Based on the performed analysis, the ligands are classified into three main groups depending on their heparin binding and oligomerization properties. The computational data agree and provide rationale for the corresponding experimental findings, contributing to the general knowledge of the physico-chemical nature of ligand-GAG intermolecular interactions.