Structural Insights into Endostatin-Heparan Sulfate Interactions Using Modeling Approaches.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Endostatins*/chemistry ; Endostatins*/metabolism ; Molecular Docking Simulation* ; Molecular Dynamics Simulation* ; Heparitin Sulfate*/chemistry ; Heparitin Sulfate*/metabolism ; Protein Binding*; Humans ; Heparin/chemistry ; Heparin/metabolism ; Collagen Type XVIII/chemistry ; Collagen Type XVIII/metabolism ; Binding Sites ; Zinc/chemistry ; Zinc/metabolism ; Models, Molecular ; Glycosaminoglycans/chemistry ; Glycosaminoglycans/metabolism ; Thermodynamics

Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling-replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn ²⁺ on endostatin-HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP's binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.

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UMO-2023/49/B/ST4/00041 National Science Center

Keywords: endostatin; glycosaminoglycans; molecular docking; protein–glycosaminoglycan interactions; repulsive scaling–replica exchange molecular dynamics

0 (Endostatins)
9050-30-0 (Heparitin Sulfate)
9005-49-6 (Heparin)
0 (Collagen Type XVIII)
J41CSQ7QDS (Zinc)
0 (Glycosaminoglycans)

Date Created: 20240914 Date Completed: 20240914 Latest Revision: 20241105

20241105

PMC11397277

10.3390/molecules29174040

39274888