Department of Pharmaceutical Sciences, University of New England College of Pharmacy, 716 Stevens Avenue, Portland, ME 04103, USA.
Graduate School of Biomedical Science and Engineering, University of Maine, 5775 Stodder Hall, Orono, ME 04469, USA.
Biomolecules. 2020 Apr 2;10(4):537. doi: 10.3390/biom10040537.
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.
糖胺聚糖（GAGs）是线性的、结构多样的、构象复杂的碳水化合物聚合物，其可能包含多达 200 个单糖。这些特性给使用现有实验方法在原子分辨率下研究 GAG 构象热力学带来了挑战。分子动力学（MD）模拟可以克服这一挑战，但仅适用于短 GAG 聚合物。为了解决这个问题，我们开发了一种算法，该算法将来自短 GAG 聚合物无偏全原子显式溶剂 MD 模拟的所有构象参数（即键长、键角和二面角）应用于 GAG 骨架柔性，从而快速构建任意长度的 GAG 模型。该算法用于生成非硫酸化软骨素 10 聚体和 20 聚体的集合，与 MD 生成的集合进行内部验证比较。构建和 MD 生成的集合中的末端到末端距离分布差异最小，表明我们的算法产生的构象集合模拟了模拟中观察到的骨架柔性。非硫酸化软骨素 100 聚体和 200 聚体的集合在一天内构建完成，证明了该算法的效率，并与模拟相比减少了时间和计算成本。
