Studying specificity in protein-glycosaminoglycan recognition with umbrella sampling

Submitting author affiliation:
University of Gdańsk, Gdańsk, Poland

Beilstein Arch. 2023, 202346.

Published 27 Oct 2023

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Glycosaminoglycan (GAG) research in the past few decades has been crucial for gaining insights into various physiological, pathological and therapeutic aspects mediated by the direct interactions between the GAG molecules and diverse proteins. The structural and functional heterogeneities of GAGs as well as their ability to bind specific proteins are determined by the sugar composition of the GAG, the size of the GAG chains, the degree and the pattern of sulfation. A deep understanding of the interactions in protein-GAG complexes is essential to explain their biological functions. In this study, the umbrella sampling approach is used to pull away a GAG ligand from the binding site and then pull it back in. We analyze the binding interactions between GAGs of three types (heparin, desulfated heparan sulfate and chondroitin sulfate) with three different proteins (basic fibroblast growth factor, acidic fibroblast growth factor and cathepsin K). The main focus of our study is to evaluate whether the umbrella sampling approach is able to reproduce experimentally obtained structures, and how useful it can be for getting a deeper understanding of GAG properties, especially protein recognition specificity and multipose binding. We find that the binding free eneergy landscape in the proximity of the GAG native binding pose is complex and implies the co-existance of several binding poses. The sliding of a GAG chain along a protein surface could be a potential mechanism of GAG particular sequence recognition by proteins.

Keywords: glycosaminoglycan; molecular docking; protein-glycosaminoglycan interaction specificity; RS-REMD; umbrella sampling

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Marcisz, M.; Sebastian, A.; Gaardløs, M.; Zacharias, M.; Samsonov, S. A. Beilstein Arch. 2023, 202346. doi:10.3762/bxiv.2023.46.v1

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