# Structural Insights into Endostatin–Heparan Sulfate Interactions Using Modeling Approaches

## TL;DR

This paper explores how endostatin interacts with heparin and heparan sulfate using advanced modeling techniques to understand its anti-tumor properties.

## Contribution

The study is the first to systematically analyze endostatin-GAG interactions using novel computational methods.

## Key findings

- Endostatin binds dynamically with heparin and heparan sulfate oligosaccharides of varying lengths and sulfation patterns.
- Key amino acid residues contributing to binding were identified through molecular dynamics simulations.
- Zn2+ was found to influence endostatin-heparin complex stability computationally.

## Abstract

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 Zn2+ 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.