Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 μs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the ⁴C₁ form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 μs unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.

中文翻译：

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使用增强的采样分子动力学鉴定水溶液中的稀有路易斯寡糖构象异构体

确定水溶液中碳水化合物配体可及的构象对于理解其生物学作用很重要。在这项工作中，我们使用群体增强型采样分子动力学（msesMD）方法的多维变体评估露水寡糖在显式水性溶剂中的构象自由能表面；我们将其与多微秒无偏MD仿真，伞形采样和加速MD方法进行了比较。对于唾液酸化的路易斯A四糖，在水溶液中的msesMD模拟可以预测与其他偏倚方法和一倍三重无偏10μs轨迹大致一致的构象态。这些模拟发现了封闭构形的优势和一系列低占用率的开放形式。⁴ C ₁表格，与以前的工作一致。对于唾液酸化的路易斯X四糖，msesMD模拟预测溶液中有少量的开放形式，与晶体学上观察到的罕见的凝集素结合姿势相对应。总体而言，通过与有偏差的MD计算进行比较，我们发现三倍的10μs无偏差MD模拟可能不足以完全采样水溶液中的聚糖构象。但是，msesMD方法的计算效率和直观方法表明了其在糖组学中作为分析寡糖构象的工具的潜力。