Abstract
Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but are only feasible for short GAG polymers. To address this problem, we developed an algorithm that applies all conformational parameters contributing to GAG backbone flexibility (i.e., bond lengths, bond angles, and dihedral angles) from unbiased all-atom explicit-solvent MD simulations of short GAG polymers to rapidly construct models of GAGs of arbitrary length. The algorithm was used to generate non-sulfated chondroitin 10- and 20-mer ensembles which were compared to MD-generated ensembles for internal validation. End-to-end distance distributions in constructed and MD-generated ensembles have minimal differences, suggesting that our algorithm produces conformational ensembles that mimic the backbone flexibility seen in simulation. Non-sulfated chondroitin 100- and 200-mer ensembles were constructed within a day, demonstrating the efficiency of the algorithm and reduction in time and computational cost compared to simulation.
Highlights
The diverse group of protein–carbohydrate conjugates called proteoglycans (PGs) is a fundamental component of tissue structure in animals and can be found in the extracellular matrix (ECM) as well as on and within cells
It has been shown that Molecular dynamics (MD) simulations can reproduce ring puckers observed by NMR [49,50,51], with one study demonstrating the capacity of the CHARMM36 force field to reproduce NMR data for an iduronate derivative in the context of a heparin analogue [51]
The conformational data described above served as inputs to an algorithm we developed to generate chondroitin polymer conformational ensembles of user-specified length and with a user-specified number of conformations
Summary
The diverse group of protein–carbohydrate conjugates called proteoglycans (PGs) is a fundamental component of tissue structure in animals and can be found in the extracellular matrix (ECM) as well as on and within cells. As an alternative approach to using CG MD to generate such conformational ensembles for GAGs, we propose using glycosidic linkage and monosaccharide ring conformations from unbiased all-atom explicit-solvent MD simulations [56,61,62,63] of short GAG polymers to rapidly construct conformational ensembles for GAGs of an arbitrary length Toward this end, we studied a non-sulfated chondroitin 20-mer with the sequence [-4 glucuronate β1-3 N-acetylgalactosamine β1-]10 for its simplicity and homogeneity. We first ran microsecond-scale all-atom explicit solvent MD on the 20-mer and used the resulting trajectories to develop a database of conformations From this database, we randomly selected individual values for the bond lengths, bond angles, and dihedral angles in the glycosidic linkages connecting glucuronate (GlcA) and N-acetylgalactosamine (GalNAc) and in the monosaccharide rings. It eliminates the need for simulation, reducing time and computational cost
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