Impact of calcium ions on the structural and dynamic properties of heparin oligosaccharides by computational analysis

Kogut, Małgorzata M.; Danielsson, Annemarie; Ricard‐Blum, Sylvie; Samsonov, Sergey A.

doi:10.1016/j.compbiolchem.2022.107727

Cited by 4 publications

(2 citation statements)

References 58 publications

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“…Similarly to the glycosidic linkage analysis, these data contribute to the understanding of the origin of the flexibility differences for the analysed GAGs, which, in turn, underlie their binding propensities. Since GAGs are negatively charged, they interact with positive ions through electrostatic attraction that could affect their conformational and binding properties [56][57][58][59]. We analysed how often each group of the analysed GAGs established contact with the counterions in the MD simulation.…”

Section: Intramolecular Interactionsmentioning

confidence: 99%

Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates

Pągielska

Samsonov

2023

Biomolecules

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Glycosaminoglycans (GAGs) are a class of linear anionic periodic polysaccharides containing disaccharide repetitive units. These molecules interact with a variety of proteins in the extracellular matrix and so participate in biochemically crucial processes such as cell signalling affecting tissue regeneration as well as the onset of cancer, Alzheimer’s or Parkinson’s diseases. Due to their flexibility, periodicity and chemical heterogeneity, often termed “sulfation code”, GAGs are challenging molecules both for experiments and computation. One of the key questions in the GAG research is the specificity of their intermolecular interactions. In this study, we make a step forward to deciphering the “sulfation code” of chondroitin sulfates-4,6 (CS4, CS6, where the numbers correspond to the position of sulfation in NAcGal residue) and dermatan sulfate (DS), which is different from CSs by the presence of IdoA acid instead of GlcA. We rigorously investigate two sets of these GAGs in dimeric, tetrameric and hexameric forms with molecular dynamics-based descriptors. Our data clearly suggest that CS4, CS6 and DS are substantially different in terms of their structural, conformational and dynamic properties, which contributes to the understanding of how these molecules can be different when they bind proteins, which could have practical implications for the GAG-based drug design strategies in the regenerative medicine.

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Section: Intramolecular Interactionsmentioning

confidence: 99%

Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates

Pągielska

Samsonov

2023

Biomolecules

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“…29 Such interactions, along with fundamental electrostatic screening effects, were presented as determining the flexibility and functional state of GAGs within cellular environments. 30,31 However, Ca 2+ simulations are prone to artifacts if electrostatic interactions are not appropriately handled. [32][33][34] This makes it unclear whether previous MD results report the real behavior of GAGs in the presence of Ca 2+ or whether they are caused by artifacts related to ill-defined electrostatic interactions.…”

Section: Introductionmentioning

confidence: 99%

Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations

Riopedre-Fernandez,

Kostal,

Martinek

et al. 2024

Preprint

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Glycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfa-tion patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, with their un-matched microscopic perspective, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics models (i.e., force fields) used in biosimulations to accurately capture sulfation-specific interactions is not well established. In this work, we evalu-ate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+to sulfated moieties — N-methylsulfamate and methylsulfate — that resemble N- and O-sulfation found in GAGs, respectively. We tested nonpolariz-able (CHARMM36 and GLYCAM06), explicitly polarizable (Drude and AMOEBA), and implicitly polarizable through charge scaling (prosECCo75 and GLYCAM-ECC75) force fields. The Ca–sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations. AIMD reveals that the preferential Ca2+binding mode to sul-fated GAG groups is solvent-shared pairing, and only the charge-scaled models agree satisfactorily with the AIMD data. All other force fields exhibit poorer performance, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields dis-play a notable shortfall in their performance, attributed to difficulties in their optimiza-tion and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, qualitatively distorting our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.

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In silico approaches for better understanding cysteine cathepsin-glycosaminoglycan interactions

Bojarski,

David,

Lecaille

et al. 2024

Carbohydrate Research

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Impact of calcium ions on the structural and dynamic properties of heparin oligosaccharides by computational analysis

Cited by 4 publications

References 58 publications

Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates

Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates

Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations

In silico approaches for better understanding cysteine cathepsin-glycosaminoglycan interactions

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