Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states

Nagarajan, Balaji; Holmes, Samuel G.; Sankaranarayanan, Nehru Viji; Desai, Umesh R.

doi:10.1016/j.sbi.2022.102356

Cited by 24 publications

(30 citation statements)

References 79 publications

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“…Recently, a number of MD studies on GAGs in water have been performed using three major forcefields, including GLYCAM, CHARMM and GROMOS [29] . Considerable insights into glycosidic torsional angles, ring puckers, inter-atomic interactions, intermolecular interactions and global shapes of GAG chains have been derived from these studies [38] . In fact, recent studies on large number of GAG disaccharides have further confirmed the classic works by Mulloy and co-workers [31] that glycosidic torsions Φ and Ψ vary within a relatively small range irrespective of sulfation pattern [39] , [40] .…”

Section: Resultsmentioning

confidence: 99%

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

Holmes

Nagarajan

Desai

2022

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

Holmes

Nagarajan

Desai

2022

Computational and Structural Biotechnology Journal

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“…20 Also, the GAG−protein interactions, either specific or nonspecific, are mainly ionic, along with hydrophobic and hydrogen-bonding interactions. 1,21 Proteins that interact with GAG are classified majorly into two groups; chemokines 22−24 and growth factors. 25,26 Examples include highly specific antithrombin (AT)−heparin interactions illuminating the anticoagulant nature of heparin 2 and GAG modulations of chemokines.…”

Section: ■ Introductionmentioning

confidence: 99%

Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study

2022

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Glycosaminoglycans (GAGs) are anionic biopolymers present on cell surfaces as a part of proteoglycans. The biological activities of GAGs depend on the sulfation pattern. In our study, we have considered three octadecasaccharide dermatan sulfate (DS) chains with increasing order of sulfation ( dp 6s, dp 7s, and dp 12s) to illuminate the role of sulfation on the GAG units and its chain conformation through 10 μs-long Gaussian accelerated molecular dynamics simulations. DS is composed of repeating disaccharide units of iduronic acid (IdoA) and N-acetylgalactosamine (N-GalNAc). Here, N-GalNAc is linked to IdoA via β(1–4), while IdoA is linked to N-GalNAc through α(1–3). With the increase in sulfation, the DS structure becomes more rigid and linear, as is evident from the distribution of root-mean-square deviations (RMSDs) and end-to-end distances. The tetrasaccharide linker region of the main chain shows a rigid conformation in terms of the glycosidic linkage. We have observed that upon sulfation (i.e., dp 12s), the ring flip between two chair forms vanished for IdoA. The dynamic cross-correlation analysis reveals that the anticorrelation motions in dp 12s are reduced significantly compared to dp 6s or dp 7s. An increase in sulfation generates relatively more stable hydrogen-bond networks, including water bridging with the neighboring monosaccharides. Despite the favorable linear structures of the GAG chains, our study also predicts few significant bendings related to the different puckering states, which may play a notable role in the function of the DS. The relation between the global conformation with the micro-level parameters such as puckering and water-mediated hydrogen bonds shapes the overall conformational space of GAGs. Overall, atomistic details of the DS chain provided in this study will help understand their functional and mechanical roles, besides developing new biomaterials.

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“…This phenomenon, depending on the range of flexibility and conformational freedom of the GAG upon binding to the protein, may be also called either plastic or non-selective binding. 24 RS-REMD simulations were also performed for 1BFC system with additional potential functions imposed on dihedral angles that compose glycosidic linkages, to check if additionally allowed flexibility of the GAG chains could lead to the improvement of the docking results. With subsequently higher replicas, the height of the energy barrier decreased.…”

Section: Rs-remd Docking Performancementioning

confidence: 99%

“…Considering that the GAGs observed in computational studies often reveal high mobility and plasticity of the binding on the protein surface 24,46 the results should be interpreted essentially differently than when analyzing binding of small drug molecules. During conventional MD runs starting from the crystal structure with the same force field parameters, observed GAG RMSD (using the crystal structure as a reference) was 4.1 Å ± 0.6 for the 1BFC complex, 5.2 ± 1.2 Å for the 2AXM dimer complex and 1.4 ± 0.3 Å for the 1E03 complex.…”

Section: Rs-remd Docking Performancementioning

confidence: 99%

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS‐REMD) in molecular modeling of protein‐glycosaminoglycan complexes

et al. 2022

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Glycosaminoglcyans (GAGs), linear anionic periodic polysaccharides, are crucial for many biologically relevant functions in the extracellular matrix. By interacting with proteins GAGs mediate processes such as cancer development, cell proliferation and the onset of neurodegenerative diseases. Despite this eminent importance of GAGs, they still represent a limited focus for the computational community in comparison to other classes of biomolecules. Therefore, there is a lack of modeling tools designed specifically for docking GAGs. One has to rely on existing docking software developed mostly for small drug molecules substantially differing from GAGs in their basic physico-chemical properties. In this study, we present an updated protocol for docking GAGs based on the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) that includes explicit solvent description. The use of this water model improved docking performance both in terms of its accuracy and speed. This method represents a significant computational progress in GAG-related research.

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Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states

Cited by 24 publications

References 79 publications

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS‐REMD) in molecular modeling of protein‐glycosaminoglycan complexes

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